Pyrazolyl-substituted heteroaryls and their use as medicaments

ABSTRACT

The invention relates to new substituted heteroaryls of formula 1 
                         
or of formula 1′
 
                         
wherein A is either N or CH,
 
wherein R 2  is selected from the group consisting of —C 1-3 -alkyl, —C 1-3 -haloalkyl, F, Br, Cl,
 
wherein Y is selected from —O— or —CH 2 —,
 
and wherein R 3  is defined as in claim  1 , and the pharmaceutically acceptable salts thereof,
 
and the use of these aforementioned compounds for the treatment of diseases such as asthma, COPD, allergic rhinitis, allergic dermatitis, lupus erythematodes, lupus nephritis and rheumatoid arthritis.

The invention relates to new substituted heteroaryls of formula 1

or of formula 1′

wherein A is either N or CH,

wherein Y is either —O— or —CH₂—

wherein R³ is a substituent in ortho- or in meta-position of thepyrazolyl-ring of formula 1 and is selected from the group consisting oflinear or branched —C₁₋₆-alkyl, —C₁₋₆-haloalkyl, —C₃₋₆-cycloalkyl,—C₁₋₄-alkylene-C₃₋₆-cycloalkyl, a five- or six-membered monocyclicheterocycle with 1, 2 or three heteroatoms each independently selectedfrom O, S or N, a nine- to 10-membered bicyclic heterocycle with 1, 2 or3 heteroatoms each independently selected from O, S or N,

wherein R³ is optionally substituted by one, two, three or foursubstituents each independently from each other selected from the groupconsisting of halogen (F), —C₁₋₃-alkyl, oxo, —CN

wherein R² is selected from the group consisting of —C₁₋₃-alkyl,—C₁₋₃-haloalkyl, F, Br, Cl, and the pharmaceutically acceptable salts ofthe aforementioned compounds.

1. BACKGROUND TO THE INVENTION

1.1 SYK-Inhibitors

The present invention describes new compounds that inhibit the proteinkinase SYK (spleen tyrosine kinase), the preparation and formulationthereof and their use for preparing a medicament.

SYK is an intracellular tyrosine kinase that has an important mediatorfunction in the signal transduction of different receptors in B-cells,mast cells, monocytes, macrophages, neutrophils, T-cells, dendriticcells and epithelial cells. The receptors in which SYK performs animportant function in signal transduction include for example thereceptors for IgE (FcεRI) and IgG (FcγR1) on mast cells and B cells, theB-cell receptor (BCR) and the T-cell receptor (TCR) on B- and T-cells,the ICAM1 receptor (ICAM1R) on epithelial cells of the respiratorytract, the DAP12-receptor on natural killer cells, dendritic cells andosteoclasts, the dectin 1-receptor on a subpopulation of T-helper cells(Th-17 cells), as well as the integrin receptors for ß1-, ß2- andß3-integrins on neutrophils, monocytes and macrophages (Wong et al.;Expert Opin. Investig. Drugs (2004) 13(7), 743-762; Ulanova et al.;Expert Opion. Ther. Target (2005) 9(5); 901-921; Wang et al.; J.Immunol. (2006) 177, 6859-6870; Leib und Gut-Landmann et al.; NatureImmunology (2007) 8, 630-638; Slack et al., European J. Immunol. (2007)37, 1600-1612). The molecular processes are described best for thesignal transduction of the FcεRI. In mast cells the binding of IgE toFcεRI causes the cross-linking of IgE-receptors and the recruiting andactivation of Lyn (a tyrosine kinase from the Src family). Active Lynphosphorylates so-called ITAM motifs, which are present in many of thereceptors listed above, and thereby generates binding sites for theSH2-domain of SYK. As a result of the binding to the ITAM motif SYK isactivated and then phosphorylates various substrates which are neededfor the release of allergic and inflammatory mediators such as e.g.histamine and 3-hexosamidase (ßHA), as well as for the synthesis oflipid mediators, such as e.g. prostaglandins and leukotrienes.

In view of its central function in different signal transductionpathways SYK has been discussed as a therapeutic target for differentdiseases such as e.g. allergic rhinitis, asthma, autoimmune diseases,rheumatoid arthritis, osteopenia, osteoporosis, COPD and variousleukaemias and lymphomas (Wong et al.; Expert Opin. Investig. Drugs(2004) 13(7), 743-762; Ulanova et al.; Expert Opion. Ther. Target (2005)9(5); 901-921; Sigh and Masuda. Annual Reports in Medicinal Chemistry(2007) Vol 42; 379-391; Bajpai et al.; Expert Opin. Investig. Drugs(2008) Vol 15 (5); 641-659; Masuda and Schmitz; PPT (2008) Vol 21;461-467; Riccaboni et al., Drug Discovery Today (2010) Vol 00 (0);517-530; Efremov and Luarenti, Expert Opin Investig Drugs. (2011)20(5):623-36).

Allergic rhinitis and asthma are diseases associated with allergicreactions and inflammatory processes and involving different cell typessuch as e.g. Mast cells, eosinophils, T-cells and dendritic cells. Afterexposure to allergens has occurred, the high affinity immunoglobulinreceptors for IgE (FcεRI) and IgG (FcγR1) are activated and induce therelease of pro-inflammatory mediators and bronchoconstrictors. Aninhibitor of the SYK kinase activity should thus be able to inhibitthese steps.

Rheumatoid arthritis (RA) is an autoimmune disease in which the bonesand ligaments structures surrounding the joints are progressivelydestroyed. In the pathophysiology of RA, B-cells play a significantrole, as has been demonstrated for example by the therapeutic use ofrituximab, a B cell-depleting antibody. In addition to the function ofSYK in the signal transduction of the BCR (which after being stimulatedalso induces the release of pro-inflammatory mediators), SYK also playsan important part in the maturation and proliferation of B cells (Chenget al. Nature (1995) 378, 303-306, Cornall et al., PNAS (2000) 97(4),1713-1718). An inhibitor of the SYK kinase activity may thus offer atherapeutic option for the treatment of autoimmune diseases such as RAand diseases with an increased proliferation of B cells, such as e.g.B-cell lymphomas.

Chronic obstructive pulmonary disease (COPD) is characterised by asuccessive deterioration in lung function and chronic inflammation ofthe airways, which is initiated and produced by noxious substances ofall kinds and contributes to the maintenance of the course of thedisease. At a cellular level, in COPD there is in particular amultiplication of T-lymphocytes, neutrophils, granulocytes andmacrophages. In particular, there is an increase in the number ofCD8-positive lymphocytes, that is directly connected with the impairmentof lung function. Another characteristic of COPD are acutedeteriorations in lung function (exacerbations), characterised by viral(e.g. Rhinovirus), or bacterial (e.g. Streptococcus pneumoniae,Haemophilus influenzae and Moraxella catarrhalis) infections.

In view of the pro-inflammatory function of SYK in macrophages, T-cellsand neutrophils as described above (see: Wong et al.; Expert Opin.Investig. Drugs (2004) 13(7), 743-762; and references cited therein) aninhibitor of the SYK kinase activity could be a new therapeutic approachto the treatment of the inflammatory processes that underlie COPD. Ithas also been shown that SYK in epithelial cells of the respiratorytract is involved in the ICAM1R-mediated uptake and subsequentreplication of the Rhinovirus and that a si-RNA against SYK blocks thesesteps (Wang et al.; J. Immunol. (2006) 177, 6859-6870; Lau et al.; J.Immunol. (2008) 180, 870-880). Thus, an inhibitor of the SYK kinaseactivity could also be used therapeutically in exacerbations caused byRhinoviruses.

Various studies suggest that SYK is involved in the malignanttransformation of lymphocytes (summarised in Sigh and Masuda, AnnualReports in Medicinal Chemistry (2007) Vol 42; 379-391). A TEL-SYK fusionprotein with a constitutive SYK activity transformed B cells of apatient with myelodysplastic syndrome, a constitutively active ITK-SYKfusion protein was isolated from patients with peripheral T-celllymphomas (PTCL). Moreover, constitutively active SYK was found inB-cell lymphoma cells of patients, especially in B-lineage acutelymphoblastic leukemia (B-ALL), follicular lymphoma (FL), diffuse largeB-cell lymphoma (DLBCL), mantle cell lymphomas and B cell Non-HodgkinLymphomas (NHLs) as well as in acute myeloid leukemia (AML). On thebasis of these data it seems that SYK is a proto-oncogene inhaematopoietic cells and represents a potential target for the treatmentof certain leukaemias and lymphomas.

Idiophathic thrombocytopenic purpura (ITP) is an autoimmune disease inwhich IgG autoantibodies against antigens present on platelets bind toand destroy platelets. Patients with ITP have an accelerated clearenceof circulating IgG-coated platelets via macrophages in the spleen andthe liver. In view of the pro-inflammatory FcγR-mediated function of SYKin macrophages an inhibitor of SYK is considered to have a therapeuticbenefit in FcγR-mediated cytopenias like ITP. Indeed the SYK inhibitorR788 (R406) improved platelet counts in a single center, oben labelstudy in patients with ITP (Podolanczuk et al; Blood (2009) 113,3154-3169).

Bullous pemphigoid (Ujiie et al. Journal of Dermatology 2010; 37:194-204) is a chronic, autoimmune, subepidermal, blistering skin diseasethat rarely involves mucous membranes. Bullous pemphigoid ischaracterized by the presence of immunoglobulin G (IgG) autoantibodiesspecific for the hemidesmosomal bullous pemphigoid antigens BP230(BPAg1) and BP180 (BPAg2). Pemphigus vulgaris (Venugopal et al.Dermatol. Clin. 2011; 29:373-80) is a chronic blistering skin diseasewith skin lesions that are rarely pruritic, but which are often painful.Pemphigus vulgaris is an autoimmune disease caused by IgG autoantibodiesdirected against both desmoglein 1 and desmoglein 3 resulting in theloss of cohesion between keratinocytes in the epidermis. It ischaracterized by extensive flaccid blisters and mucocutaneous erosions.In both diseases IgG autoantibodies bind to Fc receptor gamma (FcRγ) andactivate FcRγ and downstream signaling via SYK kinase. Thus, aninhibitor of the SYK kinase activity which blocks downstream signallingof the FcRγ could be used therapeutically to treat patients with bullouspemphigoid and pemphigus vulgaris.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease whichcan affect basically any organ of the body. It is characterised by amultisystem inflammation of the microvascular and the presence ofautoantibodies. FcγR-deficient mice are protected from several aspectsof SLE in disease-related preclinical models, suggesting that aninhibitor of SYK can have a therapeutic benefit in SLE in view of thepro-inflammatory FcγR-mediated function of SYK in various cells.

1.2 Prior Art

1,6-Naphthyridines are known as SYK-inhibitors. For example U.S. Pat.No. 3,928,367, U.S. Pat. No. 4,017,500, U.S. Pat. No. 4,115,395 and U.S.Pat. No. 4,260,759 describe 5-amino-1,6-naphthyridines with anantifungal and antibacterial activity. Further, WO 9918077 describes5-piperazinyl-1,6-naphthyridines as serotonin antagonists. Additionally,U.S. Pat. No. 7,321,041 describes substituted 1,6-naphthyridines asSYK-inhibitors, however these 1,6-naphthyridines have a completelydifferent substitution pattern from the compounds according to theinvention. Also WO 2011092128 discloses 1,6-naphthyridines which aresubstituted in 5- and in 7-position.

In WO 2012/167733, WO 2012/167423 and in WO 2012/123312 othernaphthryidine derivatives such as pyrido[3,4-b]pyrazines which were alsosubstituted in 5- and in 7-position have been disclosed asSYK-inhibitors.

Additionally, WO 01/83485 discloses substituted imidazopyrimidines andtriazolopyrimidines as SYK-inhibitors, whereas WO 2008/113469 disclosessubstituted imidazo- and triazolopyrimidines as GSK 3β-inhibitors.

Also quinolones are known as SYK-inhibitors. For instance, WO 2006038041and WO 2013014060 both disclose quinoline-compounds which aresubstituted in the 5- and 7-position, however the substitutionpattern—in particular in the 7-position—is completely different from theone of the compounds of formula 1 of the instant invention.

Additionally also PCT/EP2015055228, PCT/EP2015055237 andPCT/EP2015055242 have been filed (not yet published). Herein alsodiverse pyrazolyl-substituted heteroaryls are disclosed which are allnot substituted at the 3-position of the compounds.

Furthermore, WO2015017610 discloses also pyrazolyl-substitutedheteroaryls which all have core modifications compared to the compoundsof the instant invention.

Furthermore Thoma et al “Orally bioavailabe SYK inhibitors with activityin a rat PK/PD model”, Bioorganic & Medicinal Chemistry Letters (2015)

http://dx.doi.org/10.1016/j.bmcl.2015.08037 (article in press) has beenpublished online wherein SYK-inhibitors with similar benzo- andpyrido-thiazole/isothiazole structures are disclosed. However the mostpromising compound No. 5 with satisfying SYK-inhibitory capacities hasnot been further pursued due to the fact that compound No. 5 alsoinhibited Aurora B (AURB) which severely impaired SYK-selectivity ofcompound No. 5.

Consequently it was the aim of the instant invention to provideeffective SYK-inhibitors with excellent SYK inhibitory capacities whichalso show a sufficient SYK-selectivity.

Surprisingly it has now been found that the compounds of formulas 1 and1′ of the instant invention are particularly well suitable for thetreatment of respiratory complaints, allergic diseases, osteoporosis,gastrointestinal diseases, autoimmune diseases, inflammatory diseasesand diseases of the peripheral or central nervous system, particularlyfor the treatment of asthma, allergic rhinitis, rheumatoid arthritis,allergic dermatitis, lupus erythematosus (SLE) and COPD, in particularbecause all these compounds of the present invention show the followingdesired capacities at the same time:

-   -   high SYK inhibition (reflected by “low” IC₅₀-values with respect        to SYK-inhibition (IC₅₀-value <10 nMol in “SYK-inhibition assay”        and of EC₅₀<150 nMol in “CD63-assay”)    -   excellent SYK-selectivity that means very low inhibition of        other kinases such as Aurora B (reflected by “high” IC₅₀-values        with respect to inhibition of AURB), as FLT3 (reflected by        “high” IC₅₀-values with respect to inhibition of FLT3), as GSK3β        (reflected by “high” IC₅₀-values with respect to inhibition of        GSK3β) etc.    -   good metabolic stability which can be measured by a low        Q_(h)-percentage in human hepatocytes (% Q_(h)<20).

2. DESCRIPTION OF THE INVENTION

The instant invention refers to a compound of formula 1,

wherein A is either N or CH,

wherein Y is either —O— or CH₂,

wherein R³ is a substituent in ortho- or in meta-position of thepyrazolyl-ring of formula 1 and is selected from the group consisting oflinear or branched —C₁₋₆-alkyl, —C₁₋₆-haloalkyl, —C₃₋₆-cycloalkyl,—C₁₋₄-alkylene-C₃₋₆-cycloalkyl, a five- or six-membered monocyclicheterocycle with 1, 2 or three heteroatoms each independently selectedfrom O, S or N, a nine- to 10-membered bicyclic heterocycle with 1, 2 or3 heteroatoms each independently selected from O, S or N,

wherein R³ is optionally substituted by one, two, three or foursubstituents each independently from each other selected from the groupconsisting of halogen (F), —C₁₋₃-alkyl, oxo, —CN

wherein R² is selected from the group consisting of —C₁₋₃-alkyl,—C₁₋₃-haloalkyl, F, Br, Cl, and the pharmaceutically acceptable salts ofthe aforementioned compounds.

In a preferred embodiment the invention relates to the compounds offormula 1′

wherein A, Y, R² and R³ are defined as mentioned above,

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In further preferred embodiment the invention refers to the compounds offormula or of formula 1′,

wherein A is either N or CH

wherein Y is either —O— or CH₂,

wherein R³ is a substituent in ortho- or in meta-position of thepyrazolyl-ring of formula 1 and is selected from the group consisting ofmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,—C₁₋₆-fluoroalkyl, cyclopropyl, cyclobutyl, cyclopentyl,—C₁₋₂-alkylene-C₃₋₆-cyclopropyl, —C₁₋₂-alkylene-C₃₋₆-cyclobutyl,—C₁₋₂-alkylene-C₃₋₆-cyclopentyl, a five- or six-membered monocyclicheterocycle with 1 oxygen-atom, a 9- to 10-membered bicyclic heterocyclewith 1 or 2 heteroatoms each independently selected from O, S or N,

wherein R³ is optionally substituted by one, two, three or foursubstituents each independently from each other selected from the groupconsisting of F, Cl, Br, methyl, ethyl, —CN

wherein R² is selected from the group consisting of methyl, ethyl,isopropyl, —CF₃, F, Br, Cl, and the pharmaceutically acceptable salts ofthe aforementioned compounds.

In another preferred embodiment the invention relates to theaforementioned compounds of formula 1 or of formula 1′,

wherein A is either N or CH,

wherein Y is either —O— or —CH₂—,

wherein R³ is a substituent in ortho- or in meta-position of thepyrazolyl-ring of formula 1 and is selected from the group consisting ofmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,—(CH₂)₂—CF₃, —CH₂—CH₂F, cyclopropyl, cyclobutyl, cyclopentyl,-methylene-C₃₋₆-cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl,hexahydrofuropyranyl,

wherein R³ is optionally substituted by one, two, three or foursubstituents each independently from each other selected from the groupconsisting of F, Cl, Br, methyl, ethyl, —CN

wherein R² is selected from the group consisting of methyl and F,

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another preferred embodiment the invention refers to theaforementioned compounds of formula 1 or of formula 1′, wherein R² ismethyl, and the pharmaceutically acceptable salts of the aforementionedcompounds.

In a further preferred embodiment the invention relates to theaforementioned compounds of formula 1 or of formula 1′, wherein R² is F,and the pharmaceutically acceptable salts of the aforementionedcompounds.

In a further preferred embodiment the invention refers to theaforementioned compounds of formula 1 or of formula 1′, wherein R³ is asubstituent in meta-position of the pyrazolyl-ring of formula Land thepharmaceutically acceptable salts of the aforementioned compounds.

In another preferred embodiment the invention relates to theaforementioned compounds of formula 1 or of formula 1′, wherein R³ is asubstituent in ortho-position of the pyrazolyl-ring of formula Land thepharmaceutically acceptable salts of the aforementioned compounds.

In a further preferred embodiment the invention refers to theaforementioned compounds of formula 1 or of formula 1′, wherein R³ issubstituted by one, two, three or four substituents each independentlyfrom each other selected from the group consisting of F, methyl and —CN,and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another preferred embodiment the invention relates to theaforementioned compounds of formula 1 or of formula 1′,

wherein A is either N or CH,

wherein Y is —CH₂—,

wherein R³ is a substituent in ortho- or in meta-position of thepyrazolyl-ring of formula 1 and is selected from the group consisting ofmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,—(CH₂)₂—CF₃, —CH₂—CH₂F,

wherein R³ is optionally substituted by one, two, three or foursubstituents each independently from each other selected from the groupconsisting of F, methyl and —CN

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In a particularly preferred embodiment the invention relates to theaforementioned compound of formula 1 or of formula 1′, which is selectedfrom the group consisting of

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In a further preferred embodiment the invention refers to theaforementioned compounds of formula 1 or of formula 1′,

wherein A is either N or CH,

wherein Y is either —O— or CH₂,

wherein R³ is a substituent in ortho- or in meta-position of thepyrazolyl-ring of formula 1 and is selected from the group consisting ofisopropyl, isobutyl and t-butyl,

wherein R³ is not further substituted,

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which isselected from the group consisting of

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompound.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompound.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompound.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompound.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompound.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompound.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompound.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, wherein

wherein A is either N or CH,

wherein Y is —CH₂—,

wherein R³ is a substituent in ortho- or in meta-position of thepyrazolyl-ring of formula 1 and is selected from the group consisting of

cyclopropyl, cyclobutyl, cyclopentyl, -methylene-C₃₋₆-cyclopropyl,tetrahydrofuranyl, tetrahydropyranyl, hexahydrofuropyranyl,

wherein R³ is optionally substituted by one, two, three or foursubstituents each independently from each other selected from the groupconsisting of F, methyl and —CN

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which isselected from the group consisting of

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In another particularly preferred embodiment the invention relates tothe aforementioned compound of formula 1 or of formula 1′, which is

and the pharmaceutically acceptable salts of the aforementionedcompounds.

In a further preferred embodiment the invention relates to theaforementioned compounds for the treatment of a disease which can betreated by inhibition of the SYK enzyme.

In another preferred embodiment the invention relates to theaforementioned compounds for the treatment of a disease selected fromthe group consisting of allergic rhinitis, asthma, COPD, adultrespiratory distress syndrome, bronchitis, B-cell lymphoma, dermatitisand contact dermatitis, allergic dermatitis, allergicrhinoconjunctivitis, rheumatoid arthritis, anti-phospholipid syndrome,Berger's disease, Evans's syndrome, ulcerative colitis, allergicantibody-based glomerulonephritis, granulocytopenia, Goodpasture'ssyndrome, hepatitis, Henoch-Schönlein purpura, hypersensitivityvasculitis, immunohaemolytic anaemia, autoimmune haemolytic anemia,idiopathic thrombocytopenic purpura, Kawasaki syndrome, allergicconjunctivitis, lupus erythematodes, lupus nephritis, capsule celllymphoma, neutropenia, non-familial lateral sclerosis,artheriosclerosis, Crohn's disease, multiple sclerosis, myastheniagravis, osteoporosis, osteolytic diseases, osteopenia, psoriasis,Sjögren's syndrome, sclerodermy, T-cell lymphoma, urticaria/angiooedema,Wegener's granulomatosis, coeliac disease Waldenstroemmacroglubulinemia, systemic sclerosis (SSc), malaria and dengue.

In a further preferred embodiment the invention relates to theaforementioned compounds for the treatment of a disease selected fromthe group consisting of asthma, COPD, allergic rhinitis, adultrespiratory distress syndrome, bronchitis, allergic dermatitis, contactdermatitis, idiopathic thrombocytopenic purpura, rheumatoid arthritis,lupus erythematodes, lupus nephritis, systemic sclerosis (SSc) andallergic rhinoconjunctivitis.

In another preferred embodiment the invention relates to theaforementioned compound for the treatment of a disease selected from thegroup consisting of asthma, COPD, allergic rhinitis, idiopathicthrombocytopenic purpura, allergic dermatitis, lupus erythematodes,lupus nephritis and rheumatoid arthritis.

In a further preferred embodiment the invention relates topharmaceutical formulations, which contain one or more of theaforementioned compounds and a pharmaceutically acceptable excipient.

In another preferred embodiment the invention relates to pharmaceuticalformulations, which contain one or more of the aforementioned compoundsin combination with an active substance selected from the groupconsisting of anticholinergics, betamimetics, corticosteroids,PDE4-inhibitors, EGFR-inhibitors, LTD4-antagonists, CCR3-inhibitors,iNOS-inhibitors, CRTH2-antagonists, triple kinase inhibitors againstPDGFR, FGFR and VEGFR, HMG-CoA reductase inhibitors and NSAIDs.

In another preferred embodiment the invention relates to an intermediatecompound selected from the group consisting of formula 7

-   -   of formula 8

-   -   of formula 11

-   -   wherein R² is F or methyl,    -   wherein Y is either —O— or CH₂,    -   and wherein R³ is defined as in one of claims 1 to 3 and wherein        Hal is Cl or Br    -   and wherein PG is a protecting group selected from the group        consisting of benzyl, 1-phenylethyl, 1-(4-methoxyphenyl)ethyl.

In another preferred embodiment the invention relates to an intermediatecompound selected from the group consisting of

3. TERMS AND DEFINITIONS USED

Unless stated otherwise, all the substituents are independent of oneanother. If for example a number of C₁₋₆-alkyl groups are possiblesubstituents at a group, in the case of three substituents, for example,C₁₋₆-alkyl could represent, independently of one another, a methyl, ann-propyl and a tert-butyl.

Within the scope of this application, in the definition of possiblesubstituents, these may also be presented in the form of a structuralformula. An asterisk (*) in the structural formula of the substituent isto be understood as being the linking point to the rest of the molecule.Mor3eover, the atom of the substituent following the linking point isunderstood as being the atom in position number 1. Thus for example thegroups N-piperidinyl (I), 4-piperidinyl (II), 2-tolyl (III), 3-tolyl(IV) and 4-tolyl (V) are represented as follows:

If there is no asterisk (*) in the structural formula of thesubstituent, each hydrogen atom may be removed at the substituent andthe valency thus freed may serve as a binding site to the rest of amolecule. Thus, for example, VI

may represent 2-tolyl, 3-tolyl, 4-tolyl and benzyl.

Alternatively to the * within the scope of this application X₁ is alsounderstood as being the linking point of the group R¹ to the structureof formula 1 and X₂ as being the linking point of the group R² to thestructure of formula 1.

By the term “C₁₋₆-alkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms and by the term “C₁₋₃-alkyl” are meant branched andunbranched alkyl groups with 1 to 3 carbon atoms. “C₁₋₄-alkyl”accordingly denotes branched and unbranched alkyl groups with 1 to 4carbon atoms. Alkyl groups with 1 to 4 carbon atoms are preferred.Examples of these include: methyl, ethyl, n-propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl orhexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc., mayalso optionally be used for the above-mentioned groups. Unless statedotherwise, the definitions propyl, butyl, pentyl and hexyl include allthe possible isomeric forms of the groups in question. Thus, forexample, propyl includes n-propyl and iso-propyl, butyl includesiso-butyl, sec-butyl and tert-butyl etc.

By the term “C₁₋₆-alkylene” (including those which are part of othergroups) are meant branched and unbranched alkylene groups with 1 to 6carbon atoms and by the term “C₁₋₄-alkylene” are meant branched andunbranched alkylene groups with 1 to 4 carbon atoms. Alkylene groupswith 1 to 4 carbon atoms are preferred. Examples of these include:methylene, ethylene, propylene, 1-methylethylene, butylene,1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene,pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene,1,2-dimethylpropylene, 1, 3-dimethylpropylene or hexylene. Unless statedotherwise, the definitions propylene, butylene, pentylene and hexyleneinclude all the possible isomeric forms of the groups in question withthe same number of carbons. Thus, for example, propyl includes also1-methylethylene and butylene includes 1-methylpropylene,1,1-dimethylethylene, 1,2-dimethylethylene.

If the carbon chain is substituted by a group which together with one ortwo carbon atoms of the alkylene chain forms a carbocyclic ring with 3,5 or 6 carbon atoms, this includes, inter alia, the following examplesof the rings:

By the term “C₂₋₆-alkenyl” (including those which are part of othergroups) are meant branched and unbranched alkenyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenyl” are meant branched andunbranched alkenyl groups with 2 to 4 carbon atoms, provided that theyhave at least one double bond. Alkenyl groups with 2 to 4 carbon atomsare preferred. Examples include: ethenyl or vinyl, propenyl, butenyl,pentenyl or hexenyl. Unless stated otherwise, the definitions propenyl,butenyl, pentenyl and hexenyl include all the possible isomeric forms ofthe groups in question. Thus, for example, propenyl includes 1-propenyland 2-propenyl, butenyl includes 1-, 2- and 3-butenyl,1-methyl-1-propenyl, 1-methyl-2-propenyl etc.

By the term “C₂₋₆-alkenylene” (including those which are part of othergroups) are meant branched and unbranched alkenylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Alkenylene groupswith 2 to 4 carbon atoms are preferred. Examples of these include:ethenylene, propenylene, 1-methylethenylene, butenylene,1-methylpropenylene, 1,1-dimethylethenylene, 1, 2-dimethylethenylene,pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1, 3-dimethylpropenylene or hexenylene. Unlessstated otherwise, the definitions propenylene, butenylene, pentenyleneand hexenylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus, for example, propenylalso includes 1-methylethenylene and butenylene includes1-methylpropenylene, 1, 1-dimethylethenylene, 1, 2-dimethylethenylene.

By the term “aryl” (including those which are part of other groups) aremeant aromatic ring systems with 6 or 10 carbon atoms. Examples include:phenyl or naphthyl, the preferred aryl group being phenyl. Unlessotherwise stated, the aromatic groups may be substituted by one or moregroups selected from among methyl, ethyl, iso-propyl, tert-butyl,hydroxy, fluorine, chlorine, bromine and iodine.

By the term “aryl-C₁₋₆-alkylene” (including those which are part ofother groups) are meant branched and unbranched alkylene groups with 1to 6 carbon atoms, which are substituted by an aromatic ring system with6 or 10 carbon atoms. Examples include: benzyl, 1- or 2-phenylethyl or1- or 2-naphthylethyl. Unless otherwise stated, the aromatic groups maybe substituted by one or more groups selected from among methyl, ethyl,iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term “heteroaryl-C₁₋₆-alkylene” (including those which are partof other groups) are meant—even though they are already included under“aryl-C₁₋₆-alkylene”—branched and unbranched alkylene groups with 1 to 6carbon atoms, which are substituted by a heteroaryl.

If not specifically defined otherwise, a heteroaryl of this kindincludes five- or six-membered heterocyclic aromatic groups or5-10-membered, bicyclic heteroaryl rings which may contain one, two,three or four heteroatoms selected from among oxygen, sulphur andnitrogen, and contain so many conjugated double bonds that an aromaticsystem is formed. The following are examples of five- or six-memberedheterocyclic aromatic groups or bicyclic heteroaryl rings:

Unless otherwise stated, these heteroaryls may be substituted by one ormore groups selected from among methyl, ethyl, iso-propyl, tert-butyl,hydroxy, fluorine, chlorine, bromine and iodine.

The following are examples of heteroaryl-C₁₋₆-alkylenes:

By the term “C₁₋₆-haloalkyl” (including those which are part by of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms, which are substituted by one or more halogen atoms. By theterm “C₁₋₄-alkyl” are meant branched and unbranched alkyl groups with 1to 4 carbon atoms, which are substituted by one or more halogen atoms.Alkyl groups with 1 to 4 carbon atoms are preferred. Examples include:CF₃, CHF₂, CH₂F, CH₂CF₃.

By the term “C₃₋₇-cycloalkyl” (including those which are part of othergroups) are meant cyclic alkyl groups with 3 to 7 carbon atoms, if notspecifically defined otherwise. Examples include: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwisestated, the cyclic alkyl groups may be substituted by one or more groupsselected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy,fluorine, chlorine, bromine and iodine.

If not specifically defined otherwise, by the term “C₃₋₁₀-cycloalkyl”are also meant monocyclic alkyl groups with 3 to 7 carbon atoms and alsobicyclic alkyl groups with 7 to 10 carbon atoms, or monocyclic alkylgroups which are bridged by at least one C₁₋₃-carbon bridge.

By the term “heterocyclic rings” or “heterocycle” are meant, unlessstated otherwise, five-, six- or seven-membered, saturated, partiallysaturated or unsaturated heterocyclic rings which may contain one, twoor three heteroatoms, selected from among oxygen, sulphur and nitrogen,while the ring may be linked to the molecule through a carbon atom orthrough a nitrogen atom, if there is one. Although included by the term“heterocyclic rings” or “heterocycles”, the term “saturated heterocyclicring” refers to five-, six- or seven-membered saturated rings. Examplesinclude:

Although included by the term “heterocyclic rings” or “heterocyclicgroup”, the term “partially saturated heterocyclic group” refers tofive-, six- or seven-membered partially saturated rings which containone or two double bonds, without so many double bonds being producedthat an aromatic system is formed, unless specifically definedotherwise. Examples include:

Although included by the term “heterocyclic rings” or “heterocycles”,the term “heterocyclic aromatic rings”, “unsaturated heterocyclic group”or “heteroaryl” refers to five- or six-membered heterocyclic aromaticgroups or 5-10-membered, bicyclic heteroaryl rings which may containone, two, three or four heteroatoms, selected from among oxygen, sulphurand nitrogen, and contain so many conjugated double bonds that anaromatic system is formed, unless not specifically defined otherwise.Examples of five- or six-membered heterocyclic aromatic groups include:

Unless otherwise mentioned, a heterocyclic ring (or heterocycle) may beprovided with a keto group. Examples include:

Although covered by the term “cycloalkyl”, the term “bicycliccycloalkyls” generally denotes eight-, nine- or ten-membered bicycliccarbon rings. Examples include

Although already included by the term “heterocycle”, the term “bicyclicheterocycles” generally denotes eight-, nine- or ten-membered bicyclicrings which may contain one or more heteroatoms, preferably 1-4, morepreferably 1-3, even more preferably 1-2, particularly one heteroatom,selected from among oxygen, sulphur and nitrogen, unless notspecifically defined otherwise. The ring may be linked to the moleculethrough a carbon atom of the ring or through a nitrogen atom of thering, if there is one. Examples include:

Although already included by the term “aryl”, the term “bicyclic aryl”denotes a 5-10 membered, bicyclic aryl ring which contains sufficientconjugated double bonds to form an aromatic system. One example of abicyclic aryl is naphthyl.

Although already included under “heteroaryl”, the term “bicyclicheteroaryl” denotes a 5-10 membered, bicyclic heteroaryl ring which maycontain one, two, three or four heteroatoms, selected from among oxygen,sulphur and nitrogen, and contains sufficient conjugated double bonds toform an aromatic system, unless specifically defined otherwise.

Although included by the term “bicyclic cycloalkyls” or “bicyclic aryl”,the term “fused cycloalkyl” or “fused aryl” denotes bicyclic ringswherein the bridge separating the rings denotes a direct single bond.The following are examples of a fused, bicyclic cycloalkyl:

Although included by the term “bicyclic heterocycles” or “bicyclicheteroaryls”, the term “fused bicyclic heterocycles” of “fused bicyclicheteroaryls” denotes bicyclic 5-10 membered heterorings which containone, two, three or four heteroatoms, selected from among oxygen, sulphurand nitrogen and wherein the bridge separating the rings denotes adirect single bond. The “fused bicyclic heteroaryls” moreover containsufficient conjugated double bonds to form an aromatic system. Examplesinclude pyrrolizine, indole, indolizine, isoindole, indazole, purine,quinoline, isoquinoline, benzimidazole, benzofuran, benzopyran,benzothiazole, benzothiazole, benzoisothiazole, pyridopyrimidine,pteridine, pyrimidopyrimidine,

“Halogen” within the scope of the present invention denotes fluorine,chlorine, bromine or iodine. Unless stated to the contrary, fluorine,chlorine and bromine are regarded as preferred halogens.

Compounds of general formulas 1 or 1′ may have acid groups, mainlycarboxyl groups, and/or basic groups such as e.g. amino functions.Compounds of general formulas 1 or 1′ may therefore be present asinternal salts, as salts with pharmaceutically usable inorganic acidssuch as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonicacid or organic acids (such as for example maleic acid, fumaric acid,citric acid, tartaric acid or acetic acid) or as salts withpharmaceutically usable bases such as alkali metal or alkaline earthmetal hydroxides or carbonates, zinc or ammonium hydroxides or organicamines such as e.g. diethylamine, triethylamine, triethanolamine, interalia.

As mentioned previously, the compounds of formulas 1 or 1′ may beconverted into the salts thereof, particularly for pharmaceutical useinto the physiologically and pharmacologically acceptable salts thereof.These salts may be present on the one hand as physiologically andpharmacologically acceptable acid addition salts of the compounds offormula 1 with inorganic or organic acids. On the other hand, thecompound of formulas 1 or 1′ when R is hydrogen may be converted byreaction with inorganic bases into physiologically and pharmacologicallyacceptable salts with alkali or alkaline earth metal cations ascounter-ion. The acid addition salts may be prepared for example usinghydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid or maleic acid. It is also possible touse mixtures of the above-mentioned acids. To prepare the alkali andalkaline earth metal salts of the compounds of formulas 1 or 1′ whereinR denotes hydrogen, it is preferable to use the alkali and alkalineearth metal hydroxides and hydrides, of which the hydroxides andhydrides of the alkali metals, particularly sodium and potassium, arepreferred, while sodium and potassium hydroxide are particularlypreferred.

The compounds of general formulas 1 or 1′ may optionally be convertedinto the salts thereof, particularly for pharmaceutical use into thepharmacologically acceptable acid addition salts with an inorganic ororganic acid. Examples of suitable acids for this purpose includesuccinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid,methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid,sulphuric acid, tartaric acid or citric acid. It is also possible to usemixtures of the above-mentioned acids.

The invention relates to the compounds of formula 1 or 1′ in question,optionally in the form of the individual optical isomers, mixtures ofthe individual enantiomers or racemates, in the form of the tautomers aswell as in the form of the free bases or the corresponding acid additionsalts with pharmacologically acceptable acids—such as for example acidaddition salts with hydrohalic acids—for example hydrochloric orhydrobromic acid—or organic acids—such as for example oxalic, fumaric,diglycolic or methanesulphonic acid.

The compounds of formula 1 or 1′ according to the invention mayoptionally be present as racemates, but may also be obtained as pureenantiomers, i.e. in the (R) or (S) form. Preferred are the compoundswith the specific stereochemistry of formula 1′.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, diastereomers, mixtures ofdiastereomers, mixtures of the individual enantiomers or racemates, inthe form of the tautomers as well as in the form of the free bases orthe corresponding acid addition salts with pharmacologically acceptableacids—such as for example acid addition salts with hydrohalic acids—forexample hydrochloric or hydrobromic acid—or organic acids—such as forexample oxalic, fumaric, diglycolic or methanesulphonic acid.

The invention relates to the respective compounds of formulas 1 or 1′ inthe form of the pharmacologically acceptable salts thereof. Thesepharmacologically acceptable salts of the compounds of formulas 1 or 1′may also be present in the form of their respective hydrates (e.g.Monohydrates, dihydrates, etc.) as well as in the form of theirrespective solvates.

By a hydrate of the compound according to the formulas 1 or 1′ is meant,for the purposes of the invention, a crystalline salt of the compoundaccording to formulas 1 or 1′, containing water of crystallisation.

By a solvate of the compound according to formulas 1 or 1′ is meant, forthe purposes of the invention, a crystalline salt of the compoundaccording to formulas 1 or 1′, which contains solvent molecules (e.g.Ethanol, methanol etc) in the crystal lattice.

The skilled man will be familiar with the standard methods of obtaininghydrates and solvates (e.g. recrystallisation from the correspondingsolvent or from water).

4. METHODS OF PREPARATION

The Examples according to the invention were prepared as shown inSchemes 1, 2 or 3.

A is N, CH

Y is O, OH₂

Hal is Br or Cl

Hal¹ is Cl, F

with X being —B(OH)₂, -boronic acid pinacolester

PG is protecting group (e.g. benzyl, 1-phenylethyl,1-(4-methoxyphenyl)ethyl)

and R² and R³ are as herein before defined.

Hal is Br or Cl

with X being —B(OH)₂, -boronic acid pinacolester

PG is protecting group (e.g. benzyl, 1-phenylethyl,1-(4-methoxyphenyl)ethyl)

and R² and R³ are as herein before defined.

Hal is Br or Cl

PG is protecting group (e.g. benzyl, 1-phenylethyl,1-(4-methoxyphenyl)ethyl)

and R² and R³ are as herein before defined.

4.1. Starting Materials of Formula 2, 3, 4, 5, and 6

4.1.1. Synthesis of Compounds of Formula 2 from Scheme 1, 2 and 3

Synthesis of Synthesis of(R)-4-[(R)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one(2.1) for Examples 1, 2, 4-12, 14, 15, 17, 19 and(R)-4-[(S)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one(2.2 for Examples 13, 16, 18, 20, 21, 22 Step 1: Synthesis of(1′R,3R/S)-1-(1′-(4-Methoxyphenylethyl)-5-oxo-3-pyrrolidine carboxylicAcid (Mixture of Diastereoisomers)

A suspension of 100 g of (R)-1-(4-methoxy-phenyl)-ethylamine and 95 gitaconic acid in 0.5 L 1-methyl-2-pyrrolidinone was heated to 80° C. for1 hour. The solution was stirred for additional 4 hours at 120° C. Thereaction mixture was cooled to 25° C. and poured into 1.5 L ofdemineralized water. The precipitate was filtered, washed withdemineralized water and dried at 50° C.

Yield: 195 g (quantitative yield) solid as a Mixture of Diastereoisomers

Analysis (method G): R_(t): 2.6 min and 2.7 min, (M+H)⁺: 264

Step 2: Synthesis of(R/S)—N-Methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-carboxamideas a Mixture of Diastereoisomers

260 g of 1,1′-carbonyldiimidazole (CDI) were added to a solution of 285g (1′R,3R/S)-1-(1′-(4-methoxyphenylethyl)-5-oxo-3-pyrrolidine carboxylicacid (mixture of diastereoisomers) in 1.4 L 2-methyltetrahydrofuran at20° C. The suspension was stirred at 20° C. for 80 minutes. 235 mLethyldiisopropylamine (DIPEA) and 130 g of N,O-dimethylhydroxylaminehydrochloride were added. The suspension was stirred for 3 hours at 20°C. Under cooling 850 mL 4M hydrochloric acid was added. The organicphase was separated and washed two times with 500 mL 1 N hydrochloricacid. The aqueous phase was reextracted two times with 500 mL ethylacetate. The combined organic phases were dried over sodium sulfate.After filtration the solvent was evaporated under reduced pressure.

Yield: 271 g (82% of theory) of(R/S)—N-Methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-carboxamide(mixture of diastereoisomers) as an oil.

Analysis (method H): R_(t): 11.1 min (41 area %) and 13.8 min (59 area%), (M+H)⁺: 307

Step 3: Synthesis of(R/S)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one as aMixture of Diastereoisomers

530 mL of a 3M solution of methylmagnesium bromide in diethylether wereadded slowly to a cooled solution of 271 g of(R/S)—N-methoxy-5-oxo-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-3-carboxamide(mixture of diastereoisomers) in 1.4 L of 2-methyltetrahydrofuran sothat the temperature remained under 0° C. After complete addition thetemperature was kept for 75 minutes at 0° C. and then warmed up to 20°C. The suspension was stirred 16 hours at 20° C. Under cooling 650 mL ofa 4M hydrochloric acid were added. The organic phase was separated andwashed with 500 mL saturated sodium carbonate solution and with 500 mLsaturated brine. The organic phase was dried over sodium sulfate. Afterfiltration the solvent was evaporated under reduced pressure.

Yield: 188 g (81% of theory) of(R/S)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one(mixture of diastereoisomers) as an oil.

Analysis (method H): R_(t): 7.4 min and 9.6 min, (M+H)⁺: 262

Step 4: Crystallization of(R)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one UnderBase Induced Epimerization Conditions

103 g of a mixture of diastereoisomers(R/S)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one weredissolved in 155 mL 1-butanol at 25° C. 18 mL benzyltrimethylammoniumhydroxide (40% solution in methanol) was added. The solution was stirredfor 30 minutes at 25° C. The solution was cooled to 0° C. Precipitationstarted. The suspension was stirred for 15 minutes at 0° C. 100 mLn-heptane was added slowly and the suspension was stirred for 30 minutesat 0° C. The addition of 100 mL portions of n-heptane was repeated 4times with subsequent stirring of the suspension at 0° C. for 30minutes. The precipitate was isolated, washed with n-heptane and driedat 50° C.

Yield: 77.1 g of a beige solid (75% of theory) with a diastereoisomericpurity of ˜95:5 (method H).

For further purification the crude product was dissolved in 310 mL2-methyl-2-butanol at 40° C. (temperature <50° C.). The solution wasslowly cooled to 0° C. Precipitation started. At 0° C. 385 mL ofn-heptane were added and the suspension was stirred for 1 hour. Theprecipitate was filtrated, washed with n-heptane and dried at 50° C.

Yield: 68.7 g (67% of theory) of a colorless solid with adiastereoisomeric purity of >99:1.

Analysis (method H): R_(t): 6.8 min, (M+H)⁺: 262

Step 4: Crystallization of(R)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one UnderBase Induced Epimerization Conditions

13.2 g of a mixture of diastereoisomers(R/S)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one weredissolved in 18 mL of 1-butanol at 25° C. The solution was cooled to 3°C. and treated with 100 mg of(R)-4-Acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one. Theresulting mixture was agitated for 15 min at 3° C.; at which point, 2.3mL benzyltrimethylammonium hydroxide (40% solution in methanol) wereadded. The solution was stirred for 30 minutes at 3° C. 64 mL n-heptanewas added slowly over 1 h at 0 to 3° C. and the suspension was stirredfor 60 minutes at 0° C. The precipitate was isolated, washed withn-heptane and dried at 30° C.

Yield: 10.6 g of a beige solid (80% of theory) with a diastereoisomericpurity of ˜98:2 (method H).

Analysis (method H): R_(t): 6.8 min, (M+H)⁺: 262

Step 5: Synthesis of(R)-4-[(R)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one2.1

94.6 mg of dichloro (pentamethylcyclopentadienyl)-iridium(III) dimer and105 mg of (S,S)—N-(p-toluenesulfonyl)-1,2-diphenylethylendiamine[(R,R)-TsDPEN] were dissolved in 20 mL of acetonitrile and subsequentlycharged to a slurry of 50 g of(R)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one and 65g of sodium formate in 500 mL of water at 25° C. The slurry was heatedto 60° C. and agitated at this temperature while sparging with nitrogenfor 3 h. The reaction was diluted at 60° C. with 500 mL of isopropylacetate and subsequently cooled to ambient temperature. The layers wereseparated, and the organic portion was washed twice with 300 mL ofwater. The organic portion was concentrated to an oily solid. Theresidual material was crystallized three times from ethyl acetate andhexanes followed by drying in a vacuum oven with a nitrogen stream at30° C.

25.4 g of a beige solid with a diastereomeric purity of >99:1

Step 5: Synthesis of(R)-4-[(S)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one(2.2

9.46 mg of dichloro (pentamethylcyclopentadienyl)-iridium(III) dimer and10.52 mg of (R,R)—N-(p-toluenesulfonyl)-1,2-diphenylethylendiamine[(R,R)-TsDPEN] were dissolved in 1 mL of acetonitrile and subsequentlycharged to a slurry of 5 g of(R)-4-acetyl-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidine-2-one and 6.5g of sodium formate in 50 mL of water at 25° C. The slurry was heated to60° C. and agitated at this temperature while sparging with nitrogen for3 h. The reaction was diluted at 60° C. with 50 mL of isopropyl acetateand subsequently cooled to ambient temperature. The layers wereseparated, and the organic portion was washed with 20 mL of water. Theorganic portion was concentrated to an oil. The oil was dissolved in 8mL of isopropyl acetate at reflux. The solution was cooled to ambienttemperature wherein crystallization occurred. The mixture was diluteddropwise with 10 mL of heptane at ambient temperature. The mixture wasagitated for 30 minutes. The solids were collected by filtration, washedwith a solution of 20 vol % isopropyl acetate in heptane and dried in avacuum oven with a nitrogen stream at 55° C. 3.82 g of a beige solidwith a diastereomeric purity of 99:1

Analysis (method I): R_(t): 12.9 min, (M+H)⁺: 264

Synthesis of [(1 S)-1-[(3R)-1-[(1S)-1-(4-Methoxyphenyl)ethyl]-5-oxo-pyrrolidin-3-yl]ethyl]4-methylbenzenesulfonate(2.3 for Example 13, 16, 18, 20, 21, 22

To a mixture of(R)-4-[(S)-1-Hydroxyethyl]-1-[(S)-1-(4-methoxyphenyl)-ethyl]-pyrrolidin-2-one2.2 (20.0 g), p-toluenesulfonyl chloride (21.67 g) andN,N-dimethylpyridin-4-amine (0.92 g) was added 42 mL pyridine anddichloromethane (42 mL/DCM). The resulting mixture was stirred at 34° C.for 18 h under argon atmosphere. The reaction mixture was diluted withIsopropyl acetate and washed with water and 2M aqueous HCL. The combinedorganic phases were dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was taken up in Isopropyl acetate andn-Heptane. The precipitate was filtered off, washed withn-Heptane/Isopropyl acetate to provide of [(1 S)-1-[(3R)-1-[(1S)-1-(4-methoxyphenyl)ethyl]-5-oxo-pyrrolidin-3-yl]ethyl]4-methylbenzenesulfonate (2.3) (19.83 g) as solid.

Analysis: HPLC-MS: R_(t)=0.680 min (method J), M+H=418

Synthesis of 5-(1-Hydroxy-ethyl)-3-(4-methoxy-benzyl)-oxazolidin-2-one(2.4 for Example 3

Step 1: To (R)-2-Hydroxy-succinic acid (10 g) was added under coolingtrifluoracetic acid anhydride (25 mL) and the mixture is stirred atambient temperature. After 4 h the solution was concentrated undervacuum to which benzyl alcohol was added and the mixture was stirredover night. The solution was concentrated under vacuum (3 mbar, 60° C.)and the residual oil (28 g) was used without further purification in thenext step.

Analysis: HPLC-MS: R_(t)=0.99 min (method E), M+H=225

Step 2: The product from the previous step (23 g) was dissolved intoluene (350 mL) and Triethylamine (16 mL) and diphenylphosphorylazide(24.5 mL) was added. The mixture was stirred under reflux for 3 h, thenpartial concentrated and extracted with water (250 mL) and EtOAc (250mL). The phases were separated and the water phase was extracted twicewith EtOAc (100 mL). The combined organic phases were washed with sat.NaHCO₃, dried over MgSO₄ and concentrated. The residual was purified viaSiO₂ (Cyclohexan/EtOAc 1:2) to provide 7.4 g of a white solid.

Analysis: HPLC-MS: R_(t)=0.95 min (method E), M+H=222

Step 3: To (R)-2-Oxo-oxazolidine-5-carboxylic acid benzyl ester (1.5 g)in acetonitrile (20 mL) was added Cs₂CO₃ (3.31 g) and after 10 mins1-Bromomethyl-4-methoxy-benzene (1.86 g) and the mixture was stirred for14 h at 45° C. Water (20 mL) and DCM (60 mL) was added and the mixturestirred for 10 mins. Then the phases were separated, the organic phaseconcentrated and the product purified via prep HPLC to provide(R)-3-(4-methoxy-benzyl)-2-oxo-oxazolidine-5-carboxylic acid benzylester (349 mg) as white solid.

Analysis: HPLC-MS: R_(t)=0.85 min (X018_S03), M+H=342

Step 4: To (R)-3-(4-Methoxy-benzyl)-2-oxo-oxazolidine-5-carboxylic acidbenzyl ester (345 mg) in 2.5 mL water and dioxane (2.5 mL) was added0.485 mL LiOH (2.5N) and the mixture stirred at ambient temperature for1.5 h. Acetonitrile (10 mL), water (20 mL) and 1M aqueous HCL (1.2 mL)was added and the product lyophilized to provide a white solid (310 mg)which was used without further purification in the next step.

Analysis: HPLC-MS: R_(t)=0.52 min (X018_S01), M+H=252

Step 5: To (R)-3-(4-Methoxy-benzyl)-2-oxo-oxazolidine-5-carboxylic acid(310 mg) and dimethylhydroxylamine*HCl (210 mg) in DMF (5 mL) at 0° C.was added hydroxybenzotriazole (140 mg), N-methylmorpholine (300 μL) and1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide xHCI (200 mg) and themixture was stirred for 3.5 h. iPrOAc (50 mL) and a solution of citricacid 10%, 20 mL) was added and the phases were separated. The waterphase was extracted twice with iPrOAc (20 mL) and the combined organicphased were washed with aqueous NaHCO₃ (5%, 20 mL). The dried organicphase was concentrated and purified via prep HPLC to provide(R)-3-(4-Methoxy-benzyl)-2-oxo-oxazolidine-5-carboxylic acidmethoxy-methyl-amide (147 mg) of colourless oil.

Analysis: HPLC-MS: R_(t)=0.60 min (X018_S03), M+H=295

Step 6: To (R/S)-3-(4-methoxy-benzyl)-2-oxo-oxazolidine-5-carboxylicacid methoxy-methyl-amide (145 mg) in 2 mL THF was addedmethylmagnesiumbromide (1.4N, 490 μL) under cooling over 20 mins at −10°C. and the mixture was stirred for 30 mins. To this mixture was added 1Naqueous KHSO₄ (160 μL, NaBH₄ (56 mg) and EtOH (300 μL) at −1° C. and themixture stirred for 30 mins. Dichloromethane (20 mL) and water (15 mL)was added and the phases were separated and the water phase extractedonce with DCM. The combined organic phases were concentrated andpurified via prep HPLC (water/acetonitrile/NH₃) to provide5-(1-Hydroxy-ethyl)-3-(4-methoxy-benzyl)-oxazolidin-2-one (90 mg) 2.4 ascolourless oil containing all 4 stereoisomers in a comparable amount.

Analysis: HPLC-MS: R_(t)=0.42 min (X011_S03), M+H=250

Chiral HPLC: Chirlapak AS-H 4, 6×250 mm, 5 μm 4 ml/min,scCO₂/Isopropanol, 20 mM NH₃, 20% in 10 mins, 150 bar. R_(t)=2.577 mins(product a), R_(t)=2.986 mins (product b), R_(t)=3.362 mins (product c),R_(t)=3.655 mins (product d).

4.1.2. Synthesis of pyrazoles with formula 3 and 4

4.1.2.1. Synthesis of halogenated pyrazoles 3

Synthesis of 4-Bromo-1-tert-butyl-pyrazole (3.1) for Examples 3, 13, 15Step 1: Synthesis of 1-tert-Butyl-pyrazole

To a stirred mixture of 34.48 g of 1,1,3,3-tetramethoxy-propane and26.20 g tert.-butylhydrazine hydrochloride in 230 mL ethanol was added40.0 mL conc. hydrochloric acid dropwise below 50° C., then the mixturewas stirred under reflux for 2 h. The reaction mixture was diluted withwater. The solvent was almost removed by destillation and the aqueousresidue extracted with diethylether. The combined aqueous phases werebasified with 10N sodium hydroxide solution and extracted withdiethylether. The combined organic phases were washed with saturatedbrine, dried over sodium sulfate, filtered and concentrated in vacuo toyield 21.90 g of 1-tert-butyl-pyrazole as oil.

Analysis: HPLC-MS: R_(t)=0.412 min (method A), M+H=125

Step 2: Synthesis of 4-Bromo-1-tert-butyl-pyrazole

To a mixture of 21.9 g of 1-tert-butyl-pyrazole in 150 mL DCM was added31.5 g N-bromosuccinimide in portions between 0 and 10° C. The resultingmixture was stirred for 30 min. The reaction mixture was allowed toreach ambient temperature. The precipitate was filtered off and washedwith DCM. The combined organic extracts were washed with water andsaturated brine, dried over magnesium sulfate, filtered and concentratedin vacuo to yield 34.0 g of 4-bromo-1-tert-butyl-pyrazole as oil.

Analysis: HPLC-MS: R_(t)=1.35 min (method B), M+H=203/205

Synthesis of4-Bromo-1-(2,2,5,5-tetramethyl-tetrahydrofuran-3-yl)-1H-pyrazole (3.2)for Examples 14, 16

To a mixture of 1-(2,2,5,5-tetramethyl-tetrahydrofuran-3-yl)-1H-pyrazole(900 mg) in 15 mL DCM was added N-bromosuccinimide (830 mg) at roomtemperature. The resulting mixture was stirred for 2 h. To the reactionmixture was then added 15 mL of saturated brine. The organic phase wasdried over Na₂SO₄ filtered and concentrated in vacuo to yield 1.26 g of3.2 as oil which subsequently crystallized.

Analysis: HPLC-MS: R_(t)=0.601 min (method X018_S03), M+H=273/275

Synthesis of 2-(4-Bromo-pyrazol-1-yl)-2-methyl-propionitrile (3.3) forExample 17

Step 1: The acid (4 g) was dissolved in methanol (40 mL) andthionylchlorid (4.5 mL) was added at 10° C. The mixture was stirred overnight at room temperature, then evaporated and dissolved in DCM. Theorganic phase was extracted with aqueous sodium bicarbonate, dried overMgSO₄ and after filtration concentrated under vacuum to yield 4 gmethylester for step 2.

Analysis: MS: M+H=247/249, R_(t)=1.121 min (method Z001_005)

Step 2: The methylester (1 g) was dissolved in methanol (4 mL)containing 10% NH₃. 0.5 g calcium chloride was added and the mixturestirred for 20 h at room temperature. The mixture was concentrated anddistributed between isopropylacetat (50 mL) and water (20 mL). The waterphase was again extracted with isopropylacetat (20 mL) and the combinedorganic phases dried and concentrated under vacuum to yield 830 mgamide.

Analysis: MS: M+H=232/234, R_(t)=0.705 min (method Z018_S04)

Step 3: The amide (336 mg) was dissolved in 400 μL POCOl₃ and stirred at90° C. for 1.5 h. The reaction mixture was poured onto water and the pHwas adjusted to 7-8 via addition of aqueous NaHCO₃. The water phase wasextracted 3× with DCM and th organic phases were concentrated in vacuoto yield 284 mg 3.3.

Analysis: MS: M+H=214, R_(t)=0.58 min (method X011_S03)

Synthesis of 4-Bromo-1-(3,3-difluoro-cyclopentyl)-1H-pyrazole 3.4 forExamples 7, 22

Step 1: The 4-bromopyrazole (12 g) and 2-cyclopenten-1-one (7.1 g) wassuspended in acetonitrile (100 mL). Then scandiumtrifluoromethansulfonate (0.5 g) was added (slightly exothermic) and themixture was stirred at room temperature over night and 2 h at 40° C.

The mixture was concentrated and the yellow oil was purified via silicagel (2 kg SiO₂, gradient cyclohexane→cyclohexane:ethylacetate 7:3) toyield 16.8 g ketone.

Analysis: MS: M+H=229/231, R_(t)=0.622 min (method X018_S03)

Step 2: The ketone (5 g) was dissolved in dichloromethane (80 mL) and[Bis(2-methoxyethyl)amino]sulfurtrifluoride (45 mL, 50% in THF) wasadded in portions at 30° C. The mixture was poured onto aqueous sodiumbicarbonate solution and extracted with dichloromethane. The organicphase was washed with brine, dried over Na₂SO₄ and after filtrationconcentrated at 40 mbar to yield 3.67 g 3.4

Analysis: MS: M+H=251/253, R_(t)=0.848 min (method X018_S03)

The following halogenides were commercially available:

-   -   4-Bromo-1-(3,3,3-trifluoropropyl)-1H-pyrazole 3.5 for Examples        12    -   4-Chloro-1-(2-Fluoro-ethyl)-1H-pyrazole 3.6 for Example 11    -   4-Bromo-3-tert-butyl-1H-pyrazole 3.7 for Example 4

4.1.3. Synthesis of compounds of formula 4 (Scheme 1 and 2)

Synthesis of1-tert-Butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole(4.1) for Examples 3, 13, 15

To a stirred mixture of 4-bromo-1-tert-butyl-pyrazole 3.1 (50 g) in 230mL THF was added dropwise 2.5M N-butyllithium (100 mL, hexane) underargon atmosphere below −60° C., then the mixture was stirred at thistemperature for 5 min, before2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (52 mL) were addeddropwise below −60° C. The reaction mixture was allowed to reach ambienttemperature. The mixture was cooled with an ice bath and diluted withaqueous phosphate buffer and water and neutralized with 2M aqueoushydrochloric acid. The organic solvent was removed by destillation andthe residue was extracted with DCM. The combined organic extracts werewashed with saturated brine, dried over sodium sulfate, filtered andconcentrated in vacuo to yield1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole(44.26 g) as solid.

Analysis: HPLC-MS: R_(t)=0.904 min (method F), M+H=251

Synthesis of 3-Tert-butyl-1H-pyrazol-4-yl-4-boronic Acid (4.2) forExample 4

Step 1: 4-Bromo-3-tert-butyl-1H-pyrazole 3.7 (580 mg) was dissolved indichloromethane (20 mL) and triethylamine (477 μL) anddi-tert-butyldicarbonate (623 mg) at room temperature for 48 h. Themixture was extracted with water and the organic phase separated andconcentrated to yield 833 mg as colorless oil.

Analysis: HPLC-MS: R_(t)=0.80 min (X012_S01), M+H=249

Step 2: 4-Bromo-3-tert-butyl-pyrazole-1-carboxylic acid tert-butyl ester(369 mg) was dissolved in THF (6 mL) and cooled to −78° C. n-BuLi (837μL, 1.6M) was added and the mixture stirred for 20 min. Then2-methoxy-4,4,4,4-tetramethyl-1,3,2-dioxaborolane (239 L) was added andthe mixture was allowed to warm to room temperature over night. Waterand DCM was added to the reaction mixture and the organic phase wasseparated. The water phase was purified via prep HPLC to provide 39 mg4.2.

Analysis: HPLC-MS: R_(t)=0.47 min (X012_S01), M+H=169

The following boronic acids, boronic esters were commercially available:

-   1-(Cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole    4.4 for Example 6, 8-   1-Cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole    4.5 for Examples 5, 20-   1-Isopropyl-1H-pyrazole-4-boronic acid pinacol ester 4.6 for    Examples 2, 18-   1-Cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole    4.8 for Examples 1, 21-   4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 4.9 for    Examples 9, 10-   Isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole    4.10 for Example 19

4.1.4. Synthesis of compounds of formula 5

Synthesis of Toluene-4-sulfonic Acid(3R,3aS,7aR)-(hexahydro-furo[3,2-b]pyran-3-yl) ester (5.1) for Example10

(3R,3aR,7aR)-Hexahydro-furo[3,2-b]pyran-3-ol (300 mg) was dissolved inDichloromethane (3 mL) and pyridine (0.445 g). p-Toluene sulfonic acidchloride (0.524 g) and DMAP (15 mg) was added and the mixture stirredfor 68 h at room temperature. Then water (20 mL) and dichlormethane (20mL) was added and stirring continued for 15 min. The phases wereseparated and the organic phase concentrated. Purification was achievedvia flash chromatography on silica gel(cyclohexane→cyclohexane/ethylacetate 1:1) to provide 5.1 (0.451 g) ascolourless oil.

Analysis: HPLC-MS: R_(t)=0.52 min (X012_S01), M+H=299

The following tosylate was commercially available:

-   (S)-2,2-Dimethyltetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate    5.2 for Example 9

4.1.5. Synthesis of Heterocyclic 6 from Scheme 1, 2 and 3 Synthesis of6-Bromo-2,3-dimethyl-2H-indazol-4-ol (6.1) for Examples 8-11, 13, 16-22

Step 1: 1-Bromo-3,5-difluorobenzene (100 g) was dissolved in THF (600mL) and cooled to −78° C. LDA (300 mL, 2N in heptane/THF/ethylbenzene)was added over 20 min and the mixture stirred for 1 h. This mixture wasadded via transfer canula to acetic anhydride (250 mL, cooled to −78°C.) within 30 mins. Then the mixture was warmed to −30° C., THF wasremoved in vacuum and dichloromethane (300 mL) was added. The mixturewas basified with saturated sodium bicarbonate solution and extracted 3×with dichloromethane (300 mL). The organic phase was washed with sat.ammonia chloride solution and sat. brine, dried and concentrated at 100mbar/50° C. in vacuum. The residue was fractional destilled in vacuum at30 to 10 mbar/70-100° C. to yield 57.8 g and 74.7 g (content 80%)desired product.

Analysis: HPLC-MS: R_(t)=0.974 min (Z018_S04), M+H=235

Step 2: To 1-(4-Bromo-2,6-difluoro-phenyl)ethanone (22.05 g) dissolvedin THF (80 mL) was added hydrazine hydrate (10 mL) at ambienttemperature and the mixture was stirred over night. Water (50 mL) and2-Me-THF (70 mL) were added and the organic phase was dried andconcentrated in vacuum. The crude product was dissolved in acetonitrile(70 mL) at 80° C. and cooled to room temperature for 2 days. Theprecipitate was filtered and washed with acetonitrile and dried undervacuum for 45 min at 45° C. to provide 15.6 g white needles.

Analysis: HPLC-MS: R_(t)=0.58 min (X011_S03), M+H=229/231

Step 3: The indazole (32 g) from the previous step was suspended indichloromethane (400 mL) and trimethyloxonium tetrafluoroborate (26.75g) was added and the mixture stirred for 24 h at room temperature.Saturated sodium bicarbonate (150 mL) was added and the mixture wasbasified to pH 9 with sodium carbonate (10 mL). The precipitate wasfiltered off, the phases separated and the water phase extracted withiPrOAc. The combined organic phases were dried and concentrated invacuum to yield 33.1 g raw material which was dissolved inmethyl-tert-butyl ether (100 mL) and heated to reflux and cooled to roomtemperature. The precipitate was filtered off after 2 days to yield 6.1(22.4 g) as light yellow crystals.

Analysis: HPLC-MS: R_(t)=0.673 min (X018_S02), M+H=243/245

Synthesis of 4,6-Dichloro-2,3-dimethyl-2H-pyrazolo[4,3-c]pyridine (6.2)for Examples 3, 4, 15

Step 1: To a solution of 2,4,6-trichloro-pyridine (5.00 g) intetrahydrofuran (anhydrous, 50.00 mL) at −78° C. under a nitrogenatmosphere was added n-butyl lithium (2.5M in hexane) (10.96 ml)dropwise. The mixture was stirred at −78° C. for 1 h and thenpiperidine-1-carbaldehyde (3.04 mL) was added drop wise. The reactionwas stirred at −78° C. for 1 h. The reaction mixture was quenched withsat NH₄Cl aq (50 ml). The mixture was extracted with TBME (3×40 mL) andthe organic phase washed successively with 1M HCl (75 mL) and sat.ammonium carbonate (75 mL). The organic phase were dried (Na₂SO₄) andconcentrated and the residue purified by Biotage Isolera FCC (SiO₂: 50g) eluting with 10-50% TBME in cyclohexane to give 2.94 g of product asa yellow solid.

Analysis: HPLC-MS: R_(t)=1.27 min (method P)

¹H NMR (DMSO, 250 MHz) δ 8.07 (1H, s), 10.28 (1H, s)

Step 2: To methylmagnesium bromide (3M in diethyl ether, 3.83 mL) wasadded dropwise to a stirred solution of2,4,6-trichloro-pyridine-3-carbaldehyde (2.20 g) in tetrahydrofuran(anhydrous, 44 mL) at −78° C. under a nitrogen atmosphere. The reactionwas stirred at −78° C. for 30 mins and then allowed to warm to roomtemperature. The reaction was quenched with NH₄Cl (25 mL) andneutralised to pH 7-8 with 1M HCl. The aqueous phase was extracted withEtOAc (3×50 mL) the combined organic phase dried (Na₂SO₄) andconcentrated. The crude material was purified by Biotage Isolera (SiO₂;50 g) eluting in 0-100% EtOAc in Cyclohexane to give 1.39 g (58.7%) ascolourless oil.

Analysis: HPLC-MS: R_(t)=1.19 min (method P), M+H=226/228

¹H NMR (CDCl₃, 500 MHz) b 1.64 (3H, d, J=6.9 Hz), 2.67 (1H, d, J=9.2Hz), 5.51 (1H, d, J=6.9 Hz), 7.33 (1H, s)

Step 3: To a stirred solution of1-(2,4,6-trichloro-pyridin-3-yl)-ethanol (2.57 g) in dichloromethane(51.4 mL) was added N-methyl morpholine-N-oxide (1.994 g). The reactionwas stirred at room temperature for 10 mins after which timetetra-n-propylammonium perruthenate (TPAP) (135.6 mg) was added andstirring continued for 7 days. The mixture was filtered through celiteand the filtrate concentrated and purified by Biotage Isolera FCC (SiO₂;25 g) eluting with 7:1 cyclohexane-EtOAc to give 1.74 g as colourlessoil.

Analysis: HPLC-MS: R_(t)=1.27 min (method P), M+H=224/226

¹H NMR (CDCl₃, 500 MHz) b 2.59 (3H, s), 7.38 (1H, s)

Step 4: To a solution of 1-(2,4,6-trichloro-pyridin-3-yl)-ethanone (1.75g in ethanol, absolute (8.75 mL) was added hydrazinehydrate (0.76 mL).The reaction was stirred at room temperature over the weekend (40 h).The solvent was evaporated and water (10 mL) added. The aqueous phasewas extracted with DCM (3×10 mL), the combined organic phases were dried(Na₂SO₄) and concentrated. The crude material was purified by BiotageIsolera FCC (SiO₂; 50 g) eluting 10-30% EtOAc in cyclohexane to give0.74 g of product as an off white solid.

Analysis: HPLC-MS: R_(t)=1.15 min (method P), M+H=202/204

¹H NMR (DMSO, 500 MHz) b 2.64 (3H, s), 7.64 (1H, s)

Step 5: To a solution of4,6-dichloro-3-methyl-1H-pyrazolo[4,3-c]pyridine (550.00 mg) in dioxan(11.00 mL) under a nitrogen atmosphere was added trimethyloxoniumtetrafluoroborate (563.70 mg). The reaction was stirred at roomtemperature for 1 h. NaHCO₃ (10 mL) was added and the mixture extractedwith DCM (3×10 mL). The combined organics were dried (Na₂SO₄),concentrated and the crude residue purified by Biotage Isolera FCC(SiO₂; 10 g) 50/50 EtOAc/cyclohexane to give 380 mg of 6.2 (64.6%) as awhite solid.

Analysis: HPLC-MS: R_(t)=1.16 min (method P), M+H=216/218

¹H NMR (CDCl₃, 500 MHz) b 2.84 (3H, s), 4.10 (3H, s), 7.39 (1H, s)

Synthesis of 6-Bromo-3-fluoro-2-methyl-2H-indazol-4-ol (6.3) forExamples 1, 2, 5-7, 12, 14

Step 1: 25 g 6-Bromo-4-methoxy-1H-indazole (commercially available fromJW-Pharmlab) was suspended in 400 mL dichloromethane and 20 gtrimethyloxonium tetrafluoroborate was added and the mixture stirred for4 h at room temperature. The reaction mixture was diluted with water(300 mL), filtered via cellulose and diatomic earth and the organicphase was extracted with semi saturated aqueous sodium bicarbonate. Theorganic phase was dried and concentrated in vacuum to yield 24.6 g.

Analysis: HPLC-MS: R_(t)=0.938 min (Z018_S04), M+H=241/243

¹H NMR (DMSO, 400 MHz) b 3.90 (3H, s), 4.10 (3H, s), 6.51 (1H, s), 7.38(1H, s), 8.37 (1H, s)

Step 2: The indazole (5 g) from the previous step was dissolved in 70mLTHF and cooled to −78° C. LDA (13.5 mL, 2M in THF) was added slowlyand the mixture stirred for 30 mins after which timeN-fluorobenzenesulfonimide (9.16 g) was added. After 30 mins thereaction mixture was allowed to warm up, then water and dichloromethanewas added and the organic phase was separated and concentrated. Theresidue was dissolved in DMF/water/TFA and purified via prep HPLC toyield 2.95 g.

Analysis: HPLC-MS: R_(t)=0.56 min (X012_S01), M+H=259/261 ¹H NMR (DMSO,400 MHz) b 3.90 (3H, s), 3.94 (3H, s), 6.49 (1H, s), 7.26 (1H, s)

Step 3: 2-Fluoroindazole (2.9 g) from the previous step was dissolved inDCM (10 mL) and boron tribromide (3.24 mL) and the mixture was heatedunder reflux over night after which time water was added and the mixturewas basified with 1N NaOH. The water phase was separated, acidified with4N HCl and the precipitate was filtered off and dried at 60° C. for 2 hunder vacuum to give 6.3 (2.4 g).

Analysis: HPLC-MS: R_(t)=0.41 min (X012_S01), M+H=245/246

¹H NMR (DMSO, 400 MHz) b 3.92 (3H, s), 6.34 (1H, s), 7.08 (1H, s), 10.80(1H, s)

Synthesis of 6-Bromo-2,3-dimethyl-2H-indazol-4-ol (6.4) for Examples 13,16, 18, 20-22

Step 1: Bromo-2,6 difluoro-benzaldehyde (200 g) were dissolved in 1 L ofmethanol and Cs₂CO₃ (300 g) were added under cooling at 10° C. andstirring continued at 30° C. over night. The mixture was acidified to pH6 with aqueous HCl and the formed precipitate filtered. The precipitatewas suspended in EtOH/water 3:1 (800 mL) and dissolved in the heat andcooled to ambient temperature for 2 days. The precipitate (91 g) wascollected and purified via SiO₂ (MPLC, cyclohexan/ethylacetate 9:1) togive 65.5 g product. The mother liquor was concentrated and extractedwith DCM and also purified via SiO₂ (MPLC, cyclohexan/ethylacetate 9:1)to give 29.4 g product.

Analysis: HPLC-MS: R_(t)=0.987 min (Z018_S04)

¹H NMR (DMSO, 400 MHz) δ 3.91 (3H, s), 7.25-7.33 (2H, m), 10.23 (1H, s)

Step 2: 4-Bromo-2-fluoro-6-methoxy-benzaldehyde (65.5 g) was dissolvedin THF (250 mL) and methylmagnesiumbromide (220 mL, 1.4N in toluene/THF)was added at 0° C. and stirred for 48 h at room temperature. Additionalmethylmagnesiumbromide (60 mL, 1.4N in toluene/THF) was added andstirring continued for 4 h. The mixture was concentrated, suspended inDCM and water (50 mL) and HCl (4N, 20 mL) was added under ice cooling. Aprecipitate was filtered off, the phases were separated and the waterphase was extracted twice with DCM. The organic phases were tried andconcentrated to give 70 g product.

Analysis: HPLC-MS: R_(t)=0.950 min (Z018_S04), M+H⁺=231/233

¹H NMR (DMSO, 400 MHz) δ 1.37-1.38 (3H, d), 3.82 (3H, s), 4.95-4.96 (1H,d), 5.10-5.13 (1H, dt), 7.02-7.06 (2H, m)

Step 3: 1-(4-Bromo-2-fluoro-6-methoxy-phenyl)ethanol (90 g) wasdissolved in DCM (500 mL) and tetrapropylammoniumperruthenate (0.6 g,TPAP) and N-methyl morpholine N-oxide (42 g, NMO) and the mixturestirred for 3 h at room temperature. Additional TPAP (0.5 g) and NMO (10g) were added and the mixture stirred for 3 h after which time it wasdiluted with DCM and water and the organic phase was separated. 2,4,6Trimercaptotraizine resin (9 g, 0.5 mnol/g) were added to the organicphase and stirred for 30 mins, dried with Na₂SO₄, filtered via celluloseand diatomic earth and concentrated in vacuum to yield 100 g (content70%) product which was used in the next step without furtherpurification.

Analysis: HPLC-MS: R_(t)=0.993 min (Z018_S04), M+H⁺=247/249

¹H NMR (DMSO, 400 MHz) b 2.45 (3H, s), 3.87 (3H, s), 7.22-7.23 (2H, m)

Step 4: 100 g product (content 70%) from the previous step was suspendedin ethyleneglycol and hydrazine hydrate (200 mL) and the mixture wasstirred at 100° C. for 4 h, then at 70° C. for 48 h. The mixture waspoured onto ice water and extracted 3× with DCM. The combined organicphases were tried (Na₂SO₄) to provide 85 g product as yellow solid whichwas used in the next step without further purification.

Analysis: HPLC-MS: R_(t)=0.940 min (Z018_S04), M+H⁺=241/243

Step 5: 50 g product from the previous step was dissolved in DCM (200mL) and trimethyl-oxoniumtetrafluoroborate (30 g) was added in portionsat 0° C. and stirred overnight at room temperature. To the mixture wasadded aqueous NaHCO₃ and the pH adjusted to 9 with Na₂CO₃. The mixturewas then extracted 3× with DCM and twice with ethylacetate, the organicphases were dried and the residue purified via SiO₂ (MPLC, 2.5 kG,cyclohexane/ethylacetate 4:1) and the desired fractions combined to give18 g product.

Analysis: HPLC-MS: R_(t)=0.944 min (Z018_S04), M+H⁺=255/257

¹H NMR (DMSO, 400 MHz) b 2.66 (3H, s), 3.89 (3H, s), 3.96 (3H, s), 6.40(1H, s), 7.26 (1H, s)

Step 6: To 6-Bromo-4-methoxy-2,3-dimethyl-2H-indazole (2.3 g) in DCM (20mL) was added borontribromide (25 mL, 1M in DCM) and the mixture wasstirred for 2 h at 40° C. The mixture was concentrated and extractedwith water and DCM. The precipitate was collected and dried to provide1.62 g 6.4.

Analysis: HPLC-MS: R_(t)=0.761 min (Z018_S04), M+H⁺=241/243

¹H NMR (DMSO, 400 MHz) b 2.67 (3H, s), 3.94 (3H, s), 6.28 (1H, s), 7.08(1H, s), 10.40 (1H, s)

4.2. Synthesis of Intermediates 7, 8 and 9, from Scheme 1 and 2Synthesis of((R)-4-[(R)-1-(6-Bromo-2,3-dimethyl-2H-indazol-4-yloxy)-ethyl]-1-[(S)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-one(7.1) for Examples 8-11, 13, 16-22

6.1 (32.8 g) was dissolved in DMA (400 mL), then 2.1 (39 g) was addedand the mixture was heated to 80° C. Potassium tert-butylat (25 g) wasadded and the mixture stirred for 20 mins at 80° C. and subsequentlycooled to room temperature. Aqueous NH₄Cl (100 mL) and water (200 mL)was added. Then the mixture was extracted 3× with i-PrOAc (300 mL) andthe combined organic phases were dried over Mg₂SO₄ and evaporated underreduced pressure to yield 75.1 g (content 88%) product, from which 12 gwere purified via preparative HPLC to yield 10.0 g 7.1.

Analysis: HPLC-MS: R_(t)=0.597 min (X016_S01), M+H=486/484

¹H NMR (DMSO, 400 MHz) δ 1.16 (3H, d, J=6.1 Hz), 1.41 (3H, d, J=7.2 Hz),2.33-2.39 (1H, m), 2.44 (3H, s), 2.73 (1H, s), 2.78-2.82 (1H, m), 2.89(1H, s), 3.18 (1H, d, J=5.1 Hz), 3.49 (1H, t, J=9.2 Hz), 3.64 (3H, s),3.93 (3H, s), 4.60-4.66 (1H, m), 5.18-5.23 (1H, q, J=7.2 Hz), 6.37 (1H,s), 6.57-6.60 (2H, m), 7.09-7.11 (2H, m), 7.21 (1H, d, J=1.2 Hz)

Alternatively 7.1 was synthesized the following:

6-Bromo-2,3-dimethyl-2H-indazol-4-ol 6.4 (10.5 g), potassium carbonate(16.8 g) and 2.3 (18.6 g) were suspended in anhydrous DMF and stirredfor 2 h at 70° C. and over night at 50° C. Additional 2.3 (5 g) andpotassium carbonate (5 g) were added and the mixture stirred for 3 h at70° 0. The mixture was concentrated, water and DCM was added and thewater phase was extracted 3× with DCM (250 mL). The organic phase waswashed with KHSO₄ and dried (Na₂SO₄) and concentrated. The mixture waspurified via SiO₂ (DCM: MeOH 9:1) to give 12.7 g 7.1

Analysis: HPLC-MS: R_(t)=1.029 min (Z018_S04), M+H=486/488

¹H NMR (DMSO, 400 MHz) δ 1.16 (3H, d, J=6.1 Hz), 1.41 (3H, d, J=7.2 Hz),2.33-2.39 (1H, m), 2.44 (3H, s), 2.73 (1H, s), 2.78-2.82 (1H, m), 2.89(1H, s), 3.18 (1H, d, J=5.1 Hz), 3.49 (1H, t, J=9.2 Hz), 3.64 (3H, s),3.93 (3H, s), 4.60-4.66 (1H, m), 5.18-5.23 (1H, q, J=7.2 Hz), 6.37 (1H,s), 6.57-6.60 (2H, m), 7.09-7.11 (2H, m), 7.21 (1H, d, J=1.2 Hz)

Synthesis of(R)-4-[(R)-1-(6-Chloro-2,3-dimethyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)-ethyl]-1-[(S)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-one(7.2) for Examples 3, 4, 15

2.1 (3.2 g) was dissolved in THF (50 mL) and NaH (1.08 g, 60% dispersionin mineral oil) was added and the mixture stirred for 5 mins, then 6.2(2.5 g) was added and stirring continued at 50° C. for 3 h. Aftercooling, aqueous NH₄Cl (50 mL) was added and the mixture extracted 2×with iPrOAc and the combined organic phases dried (MgSO₄) andconcentrated. The product was purified via prep HPLC to give 7.2 (3.65g) as white solid.

Analysis: HPLC-MS: R_(t)=0.60 min (X012_S01), M+H=443

¹H NMR (DMSO, 400 MHz) b 1.22 (3H, d, J=6.2 Hz), 1.40 (3H, d, J=7.2 Hz),2.37-2.43 (1H, m), 2.45 (3H, s), 2.51-2.56 (1H, m), 2.64-2.72 (1H, m),2.76-2.80 (1H, m), 3.53 (1H, t, J=9.3 Hz), 3.62 (3H, s), 3.96 (3H, s),5.16-5.18 (1H, q, J=7.2 Hz), 5.33-5.35 (1H, m), 6.47-6.49 (2H, m),7.01-7.03 (3H, m)

Synthesis of(1R,4R)-4-[(R)-1-(6-Bromo-3-fluoro-2-methyl-2H-indazol-4-yloxy)-ethyl]-1-[1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-one(7.3) for Examples 1, 2, 5-7, 12, 14

2.4 g 6.3 was dissolved in DMF (20 mL), potassium carbonate (5.41 g) and2.3 (6.13 g) was added and the mixture stirred at 70° C. over night. Themixture was concentrated in vacuum, water was added and the mixture wasextracted 3× with DCM. The organic phase was separated to yield 5.5 g(content 80%) product 7.3 which was used without further purification inthe next step.

Analysis: HPLC-MS: R_(t)=0.61 min (X012_S01), M+H=490/492

Synthesis of(R)-5-[(R)-1-(6-Chloro-2,3-dimethyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)-ethyl]-3-(4-methoxy-benzyl)-oxazolidin-2-one(7.4) for Examples 3

To 6.2 (75 mg) and NaH (32 mg) was added 2.4 (90 mg) dissolved indimethylacetamide (DMA; 2 mL) and the solution was stirred for 5 h. Themixture was purified via prep HPLC (water/acetonitril/NH₃) to provide7.4 (38 mg) and 7.5 (46 mg) as white solids. (7.4 and 7.5 as mixture ofenantiomers)

Analysis 7.4: HPLC-MS: R_(t)=0.83 min (X018_S03), M+H=431

Analysis 7.5: HPLC-MS: R_(t)=0.87 min (X018_S03), M+H=431

Synthesis of(R)-4-[(R)-1-(6-Bromo-2,3-dimethyl-2H-indazol-4-yloxy)-ethyl]-pyrrolidin-2-one(8.1) for Examples 8, 13, 18, 19, 20

A mixture of 7.1 (2.3 g) in TFA (40 mL) and anisole (5 mL) was stirredat 80° C. for 15 h and 8 h at room temperature. The reaction mixture wasconcentrated, diluted with acetonitrile (8 mL), basified with 25% NH₃and diluted with water and separated via prep HPLC. The yellow oil wasdissolved in Methyl tert-butyl ether and formed a white precipitatewhich was collected after 3 days to give 8.1 (1.35 g).

Analysis: HPLC-MS: R_(t)=0.45 min (X012_S01), M+H=352/354

¹H NMR (DMSO, 400 MHz) b 1.28 (3H, d, J=6.1 Hz), 2.15-2.35 (2H, m), 2.63(3H, s), 2.72-2.82 (1H, m), 3.07-3.11 (1H, m), 3.37 (1H, t, J=8.9 Hz),3.95 (3H, s), 4.63-4.69 (1H, m), 6.45 (1H, s), 7.23 (1H, d, J=1.0 Hz),7.55 (1H, s)

Synthesis of(R)-4-[(R)-1-(6-Chloro-2,3-dimethyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy)-ethyl]-pyrrolidin-2-one(8.2) for Examples 4, 15

7.2 (2.4 g, content 85%) was stirred in TFA (20 mL) at 80° C. for 4 hafter which time it was concentrated. The residual was dissolved iniPrOAc and sat. aqueous NaHCO₃ (30 mL) and water (20 mL) was added. Theprecipitate was collected, washed with water, iPrOAc and petrol ether toprovide 890 mg white solid 8.2.

Analysis: HPLC-MS: R_(t)=0.48 min (X012_S02), M+H=309

¹H NMR (CDCl₃, 500 MHz) b 1.41 (3H, d, J=6.3 Hz), 2.43-2.57 (2H, m),2.86 (1H, ddd, J=14.1, 8.3, 6.0 Hz), 3.32 (1H, dd, J=9.6, 6.4 Hz), 3.55(1H, t, J=9.1 Hz), 4.00 (3H, s), 5.59 (1H, m), 5.72 (1H, s), 7.03 (1H,s)

Synthesis of(R)-4-[(R)-1-(6-Bromo-3-fluoro-2-methyl-2H-indazol-4-yloxy)-ethyl]-pyrrolidin-2-one(8.3) for Examples 1, 2, 5, 6

A mixture of 7.3 (2.8 g) in 10 mL TFA was stirred at 80° C. for 2 h. Thereaction mixture was poured in water, basified with NaOH (4N) andextracted with DCM. The organic phase was concentrated and purified viaSiO₂ and the desired fractions were combined to give 8.3 (0.868 g).

Analysis: HPLC-MS: R_(t)=0.46 min (X012_S02), M+H=357/359

4.1.6. Synthesis of boronic acids and boronic esters 9 and 12 fromScheme 1 and 2 Synthesis of(R)-4-{(R)-1-[2,3-Dimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazol-4-yloxy]-ethyl}-1-[(S)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-one(9.1) for Examples 11, 16, 17, 22

7.1 (50 mg), bis-(pinacolato)-diboron (31 mg),tetrakis(triphenylphosphine palladium(0) (24 mg) and potassium acetate(30 mg) were suspended in dioxane (2 mL) and the mixture stirred at 100°C. for 1.5 h. The mixture was diluted with DCM (20 mL) and water (20 mL)and the organic phase was separated and concentrated to yield 9.1 (84mg, content 50%) as oil, which was used in the next step without furtherpurification.

Analysis: HPLC-MS: R_(t)=0.41 (acid)+0.61 (ester, 9.1) min (X016_S01),M+H=452 and 534

Synthesis of(R)-4-{(R)-1-[3-Fluoro-2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazol-4-yloxy]-ethyl}-pyrrolidin-2-one(12.1) for Example 12, 14

8.3 (400 mg), bis-(pinacolato)-diboron (342 mg) and potassium acetate(330 mg) and were suspended in dioxane (5 mL) and degassed with nitrogenfor 5 min.

(2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (95 mg) was added and the mixture stirred at 75° C.over night after which time it was filtered via Agilent StratoSpheresPL-Thiol MP SPE using MeOH as eluent and concentrated to yield 12.1 (400mg) as oil which was used without further purification.

Analysis: HPLC-MS: Rt=0.51 min M+H: 404 (method X012_S01).

4.3 Synthesis of the Patent Examples of Formula 1 Via Intermediates withFormula 8-11 Synthesis of(R)-4-{(R)-1-[6-(1-Cyclobutyl-1H-pyrazol-4-yl)-3-fluoro-2-methyl-2H-indazol-4-yloxy]-ethyl}-pyrrolidin-2-one(Example 1)

To 8.3 (70 mg) in dioxan (1 mL) and 2M aqueous Na₂CO₃ (295 μL) was addedborolane 4.8 (48.7 mg) and1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (A), 7.2 mg)and the mixture was stirred for 45 mins at 70° C. The mixture wasfiltered via Agilent StratoSpheres PL-Thiol MP SPE using MeOH as eluentand purified via prep HPLC to yield after lyophilisation 43 mg ofExample 1.

Analysis: HPLC-MS: R_(t)=0.68 min (001_CA02), M+H=398

¹H NMR (DMSO, 400 MHz) b 1.31 (3H, d, J=6.1 Hz), 1.78-1.85 (2H, m),2.17-2.32 (2H, m), 2.38-2.44 (3H, m), 2.75-2.77 (1H, m), 3.09-3.13 (1H,m), 3.37 (1H, t, J=9.0 Hz), 3.92 (3H, s), 4.73-4.85 (2H, m), 6.66 (1H,s), 7.18 (1H, s), 7.53 (1H, s), 7.96 (1H, s), 8.33 (1H, s)

The following examples were synthesized in anlogous manner to Example 1using the following palladium catalyst systems:

Boronic acid/ ester (corresponding to Yield Example formula 8 formula 4)catalyst Analysis Example 2 8.3 1-Isopropyl-4-  39 mg HPLC-MS:(R)-4-{(R)-1-[3-Fluoro- (4,4,5,5- (51%) R_(t) = 0.64 min6-(1-isopropyl-1H- tetramethyl-1,3,2- A) (001_CA02)M + H = 386pyrazol-4-yl)-2-methyl- dioxaborolan-2- 2H-indazol-4-yloxy]- yl)pyrazole4.6 ethyl}-pyrrolidin-2-one Example 4 8.2 3-Tert-butyl-1H-  15 mgHPLC-MS: (R)-4-{(R)-1-[6-(3-tert- pyrazol-4-yl-4- (32%) R_(t) = 46 min(X012_S01) Butyl-1H-pyrazol-4-yl)- boronic acid 4.2 B) M + H = 3972,3-dimeth-yl-2H- ¹H NMR (DMSO, 400 pyrazolo[4,3-c]pyridin- MHz) δ 1.30(9H, s), 1.36 4-yloxy]-ethyl}- (3H, d, J = 6.2 Hz), 2.22-pyrrolidin-2-one 2.35 (2H, m), 2.65 (3H, s) 2.75-2.84 (1H, m), 3.12-3.17(1H, m), 3.40 (2H, t, J = 9.0 Hz), 3.98 (3H, s), 5.66-5.71 (1H, m), 6.59(1H, s), 7.42 (1H, s), 7.53 (1H, s) Example 5 8.3 1-Cyclopropyl-4-  44mg HPLC-MS: (R)-4-{(R)-1-[6-(1- (4,4,5,5- (58%) R_(t) = 0.62 minCycloprop-yl-1H- tetramethyl- A) (001_CA02), pyrazol-4-yl)-3-fluoro-2-[1 ,3,2] M + H = 384 methyl-2H-indazol-4- dioxaborolan-yloxy]-ethyl}-pyrrolidin- 2-yl)-1H- 2-one pyrazole 4.5 Example 6 8.31-(Cyclopropyl-  47 mg HPLC-MS: (R)-4-{(R)-1-[6-(1- methyl)-4- (60%)R_(t) = 0.66 min Cycloprop-ylmethyl-1H- (4,4,5,5- A) (001_CA02),pyrazol-4-yl)-3-fluoro-2- tetramethyl-1,3,2- M + H = 398methyl-2H-indazol-4- dioxaborolan-2- yloxy]-ethyl}-pyrrolidin-yl)-1H-pyrazole 2-one 4.4 Example 8 8.1 1-(Cyclopropyl-  22 mg HPLC-MS:(R)-4-{(R)-1-[6-(1- methyl)-4- (40%) R_(t) = 0.55 minCyclopropylmethyl-1H- (4,4,5,5-tetra- A) (X011_S03), pyrazol-4-yl)-2,3-methyl-1,3,2- M + H = 395 dimethyl-2H-indazol-4- dioxaborolan-2-yloxy]-ethyl}-pyrrolidin- yl)-1H-pyrazole 2-one 4.4 Example 13 8.11-tert-Butyl-4- 120 mg HPLC-MS: (R)-4-{(R)-1-[6-(1-tert- (4,4,5,5- (47%)R_(t) = 0.51 min Butyl-1H-pyrazol-4-yl)- tetramethyl-1,3,2- A)(X018_S01), M + H = 396 2,3-dimethyl-2H- dioxaborolan-2-yl) ¹H NMR(DMSO, 400 indazol-4-yloxy]-ethyl}- pyrazole 4.1 MHz) δ 1.32 (3H, d,pyrrolidin-2-one J = 6.0 Hz), 1.56 (9H, s), 2.20-2.38 (2H, m), 2.63 (3H,s) 2.75-2.85 (1H, m), 3.12-3.16 (1H, m), 3.40 (1H, t, J = 9.1 Hz), 3.94(3H, s), 4.75-4.80 (1H, m), 6.59 (1H, s), 7.57 (1H, s), 7.89 (1H, s),8.26 (1H, s) Example 15 8.2 1-tert-Butyl-4- 630 mg HPLC-MS:(R)-4-{(R)-1-[6-(1-tert- (4,4,5,5- (60%) R_(t) = 0.48 minButyl-1H-pyrazol-4-yl)- tetramethyl-1,3,2- A) (X012_S01),2,3-dimethyl-2H- dioxaborolan-2- M + H = 397 pyrazolo[4,3-c]pyridin-yl)pyrazole 4.1 ¹H NMR (MeOD, 500 4-yloxy]-ethyl}- MHz) δ 1.47 (3H, d,pyrrolidin-2-one J = 6.3 Hz), 1.63 (9H, s) 2.54 (2H, dd, J = 8.2, 5.1Hz), 2.70 (3H, s), 2.88- 2.99 (1H, m), 3.36 (1H, dd, J = 10.1, 5.8 Hz),3.59 (1H, dd, J = 10.0, 8.7 Hz), 4.00 (3H, s), 5.72 (1H, p, J = 6.2 Hz),7.16 (1H, s), 8.18 (1H, s) Example 18 8.1 1-Isopropyl-4- 430 mg HPLC-MS:(R)-4-{(R)-1-[6-(1- (4,4,5,5-tetra- (99%) R_(t) = 0.52 minIsopropyl-1H-pyrazol-4- methyl-1,3,2- B) (X018_S03),yl)-2,3-dimethyl-2H- dioxaborolan-2- M + H = 382indazol-4-yloxy]-ethyl}- yl)pyrazole 4.6 ¹H NMR (DMSO, 400pyrrolidin-2-one MHz) δ 1.32 (3H, d, J = 6.1 Hz), 1.46 (6H, d, J = 6.7Hz), 2.19-2.37 (2H, m), 2.63 (3H, s), 2.75- 2.85 (1H, m), 3.11-3.15 (1H,m), 3.40 (1H, t, J = 9.1 Hz), 3.95 (3H, s), 4.47-4.53 (1H, m), 4.74-4.80 (1H, m), 6.59 (1H, s), 7.20 (1H, s), 7.58 (1H, s), 7.89 (1H, s),8.23 (1H, s) Example 19 8.1 1-Isobutyl-4- 242 mg HPLC-MS:(R)-4-{(R)-1-[6-(1- (4,4,5,5- (98%) R_(t) = 0.43 minIsobutyl-1H-pyrazol-4- tetramethyl-1,3,2- B) (X017_S01),yl)-2,3-dimethyl-2H- dioxaborolan-2- M + H = 396indazol-4-yloxy]-ethyl}- yl)-1H-pyrazole pyrrolidin-2-one 4.10 Example20 8.1 1-Cyclopropyl-4-  23 mg HPLC-MS: (R)-4-{(R)-1-[6-(1- (4,4,5,5-(35%) R_(t) = 0.58 min Cyclopropyl-1H- tetramethyl- A) (003_CA04),pyrazol-4-yl)-2,3- [1,3,2] M + H = 381 dimethyl-2H-indazol-4-dioxaborolan- yloxy]-ethyl}-pyrrolidin- 2-yl)-1H- 2-one pyrazole 4.5Example 21 8.1 1-Cyclobutyl-4- 145 mg HPLC-MS: (R)-4-{(R)-1-[6-(1-(4,4,5,5- (65%) R_(t) = 0.57 min Cyclobutyl-1H-pyrazol-tetramethyl-1,3,2- (X018_S03), 4-yl)-2,3-dimethyl-2H- dioxaborolan-2-M + H = 394 indazol-4-yloxy]-ethyl}- yl)-1H-pyrazole pyrrolidin-2-one4.8 A) 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) or B)Dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane[2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium

Example 13 was alternatively synthesized via the following synthesisprocedure:

Step 1: Isopropyl magnesium chloride lithium chloride complex (1.3 M inTHF, 28.4 mL, 37 mmol) was charged to a solution of4-bromo-1-(tert-butyl)-1H-pyrazole (5.0 g, 25 mmol) in anhydrous THF (25mL) under argon at ambient temperature. Anhydrous dioxane (3.3 g, 37mmol) was charged to the reaction, and the reaction was agitated at 45°C. for 4 h. The resulting mixture was cooled to ambient temperature andcharged to an anhydrous solution of acetic anhydride (7.5 g, 73 mmol) inTHF (25 mL) at −20° C. The resulting mixture was warmed to ambienttemperature and concentrated to a residue. The mixture was dissolved inmethyl t-butyl ether (50 mL) and washed with water (25 mL). The organicportion was concentrated to provide crude1-(1-(tert-butyl)-1H-pyrazol-4-yl)ethan-1-one as an oil (7.6 g, 36 wt %)and 67% yield. Crystallization in a mixture of methyl t-butyl ether andheptane provided analytically pure material1-(1-(tert-Butyl)-1H-pyrazol-4-yl)ethan-1-one. ¹H NMR (500 MHz, CDCl₃)δ=7.96 (s, 1H), 7.86 (s, 1H), 2.37 (s, 3H), 1.55 (s, 9H).

Step 2: Degassed 1,4 dioxane (10 mL) was charged to a mixture ofpalladium acetate (51 mg, 0.23 mmol), tri-t-butylphosphoniumtetrafluoroborate (128 mg, 0.44 mmol), lithium t-butoxide (1.47 g, 18mmol), 3-iodo-1,5-dimethyl-1H-pyrazole-4-carboxylic acid (1.0 g, 3.7mmol, Organic Letters (2015), 17(12), 2964-2967) and1-(1-t-butyl)-1H-pyrazole-4-yl)ethan-1-one (0.68 g, 4.1 mmol) at ambienttemperature under argon. The agitated mixture was heated to 80° C. overapproximately 15 min and stirred at this temperature for 30 min. Thereaction was cooled to ambient temperature and diluted withtrifluoroacetic acid (30 ml) and acetonitrile (15 mL). The mixture wasagitated at 78° C. for 10 h. The reaction was cooled to ambienttemperature and concentrated to a solid residue. The residue wasdissolved in a mixture of isopropyl acetate and water. The aqueous layerpH was adjusted to pH ˜10 with 3M NaOH.

The layers were separated, and the organic portion was washed twice withwater. The organic portion was concentrated to a solid (1.92 g). Thesolid was dissolved in hot n-propanol (7 mL) and cooled to ambienttemperature wherein crystallization occurred. The mixture was dilutedwith water (10 mL) dropwise and agitated for 30 min. The solids werecollected by filtration and washed with a solution of 20 vol %n-propanol in water. The solids were dried in a vacuum oven at 50° C.with a nitrogen stream to provide6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2,3-dimethylpyrano[4,3-c]pyrazol-4(2H)-oneas a solid in ˜94 wt % purity (49% yield). ¹H NMR (CDCl₃, 400 MHz),δ=7.96 (s, 1H), 7.83 (s, 1H), 6.61 (s, 1H), 3.89 (s, 3H), 2.66 (s, 3H),1.62 (s, 9H).

Step 3: Dimethyl methylphosphonate (1.2 g, 10 mmoL) was charged dropwiseto an anhydrous slurry of lithium diisopropyl amide (2.0 M, 4.6 mL, 9.2mmol) in THF (15 mL) at −78° C. under argon. After agitation for 50 min,an anhydrous slurry of6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2,3-dimethylpyrano[4,3-c]pyrazol-4(2H)-one(0.89 g, 3.11 mmol) in THF (10 mL) was charged to the above lithiatedphosphonate solution at −78° C. The reaction mixture was agitated at−78° C. for 1 h and allowed to warm to ambient temperature over 1 h. Thereaction was quenched with methanol (3 mL) and agitated for 1 h. Aqueous3 M HCl (4 mL) was charged to the reaction, and the reaction wasagitated overnight at ambient temperature. The reaction was diluted withwater (15 mL) and concentrated in vacuo to remove the organic solvents.The resulting slurry was diluted with isopropyl acetate and water. Theaqueous layer pH was adjusted to 3-4 with 3 M HCl. The layers wereseparated, and the aqueous portion was back extracted with isopropylacetate. The combined organic layers were concentrated to a solid invacuo. The solid was dissolved in hot n-propanol (6 mL), cooled toambient temperature and diluted with water (35 mL) dropwise withstirring. The mixture was agitated for 1 h at ambient temperature. Thesolids were collected by filtration washed with water, and dried in avacuum oven at 50° C. with a nitrogen stream to provide6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2,3-dimethyl-2H-indazol-4-ol (760 mg,84 wt %, 72% yield). ¹H NMR (DMSO-d6, 400 MHz), δ=9.86 (s, 1H), 8.11 (s,1H), 7.75 (s, 1H), 7.11 (s, 1H), 6.41 (s, 1H), 3.94 (s, 3H), 2.67 (s,3H), 1.55 (s, 9H).

Step 4: A mixture of potassium carbonate (610 mg, 4.4 mmol),(S)-1-((R)-1-((S)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethyl4-methylbenzenesulfonate (810 mg, 1.9 mmol), and6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2,3-dimethyl-2H-indazol-4-ol (418 mg,1.5 mmol) in anhydrous dimethyl formamide (1.5 mL) were agitated undernitrogen at 70° C. for 18 h. Additional(S)-1-((R)-1-((S)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethyl4-methylbenzenesulfonate (0.280 mg, 0.66 mmol) was charged to thereaction, and the reaction was agitated at 70° C. for 20 h. The reactionwas diluted with isopropyl acetate and water. The layers were separated,and the organic portion was washed twice. The organic portion wasconcentrated to an oily solid. Purification by silica gel chromatography(Methanol in ethyl acetate) provided the intended product(R)-4-((R)-1-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2,3-dimethyl-2H-indazol-4-yl)oxy)ethyl)-1-((S)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one(10.5) as a foam in approximately 90% purity (769 mg, 89%). ¹H NMR(CDCl₃, 500 MHz), δ=7.77 (s, 1H), 7.72 (s, 1H), 7.24 (s, 1H), 7.15 (d,J=8.74 Hz, 2H), 6.23 (d, J=8.54 Hz, 2H), 6.26 (s, 1H), 5.46 (q, J=7.41Hz, 1H), 4.50-4.56 (m, 1H), 3.97 (s, 3H), 3.69 (s, 3H), 3.48 (t, J=9.0Hz, 1H), 2.93-3.0 (m, 1H), 2.62-2.80 (m, 2H), 2.55-2.62 (m, 1H), 2.48(s, 3H), 1.64 (s, 9H), 1.50 (d, J=7.4 Hz, 3H), 1.31 (d, J=6.3 Hz, 3H).

Step 5: A solution of(R)-4-((R)-1-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2,3-dimethyl-2H-indazol-4-yl)oxy)ethyl)-1-((S)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one(585 mg, 1.1 mmol) in trifluoroacetic acid (3 mL) and anisole (1.5 mL)was agitated at 75° C. under nitrogen for 18 h. The reaction was cooledto ambient temperature and diluted with isopropyl acetate and water. Theaqueous portion pH was adjusted to 6 with aqueous 3M NaOH. The layerswere separated and the organic portion was concentrated to an oil.Purification by silica gel chromatography (EtOH in EtOAc) providedexample 13 as a foam (420 mg, 94%).

Synthesis of(R)-5-{(R)-1-[6-(1-tert-Butyl-1H-pyrazol-4-yl)-2,3-dimethyl-2H-pyrazolo[4,3-c]pyridin-4-yloxy]-ethyl}-oxazolidin-2-one(Example 3)

Step 1: To 4.1 (46 mg) and dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium(15 mg) was added 7.4 (38 mg), dissolved in dioxane (1 mL) and MeOH (0.2mL) and 2M aqueous Na₂CO₃ (0.175 mL), and the mixture was heated for 50mins at 90° C. After which time MeOH (10 mL) was added and the mixturewas filtered via Agilent StratoSpheres PL-Thiol MP SPE and concentrated.The residual was dissolved in DCM (20 mL) and extracted with water (20mL) and the water phase extracted with DCM (10 mL). The combined organicphases were dried and concentrated to yield 10.1 (74 mg) which was usedwithout further purification for the next step.

Analysis: HPLC-MS: R_(t)=0.86 min (X018_S03), M+H=519

Step 2: To 10.1 (74 mg) was added trifluoracetic acid (2.956 g) and themixture was stirred for 30 h at 75° C. The mixture was then concentratedand purified via prep HPLC (water/acetonitrile/NH₃) to provide a whitesolid which was then separated via Chiral SFC (Knauer Eurocel 01; 80%scCO₂/20% MeOH+20 mM NH₃; 120 bar BPR; 40° C. to provide Example 3 (13mg) as white solid.

Analysis: HPLC-MS: R_(t)=0.92 min (V011_S01), M+H=399

Synthesis of(R)-4-((R)-1-{6-[1-((R)-2,2-Dimethyl-tetrahydro-pyran-4-yl)-1H-pyrazol-4-yl]-2,3-dimethyl-2H-indazol-4-yloxy}-ethyl)-pyrrolidin-2-one(Example 9)

Step 1: To 7.1 (200 mg),4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole 4.9 (120mg), Dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane[2-(2-aminophenyl) phenyl]-methylsulfonyloxy-palladium (40 mg) was addeddioxane (3 mL) and 2M aqueous Na₂CO₃ (0.7 mL) and the mixture wasstirred for 2 h at 90° C. The mixture was diluted with DCM (50 mL) andwater (30 mL). After phase separation the water phase was extracted 2×with DCM (25 mL). The combined organic phases were dried (MgSO₄) andpurified via prep HPLC to provide 11.1 as yellow oil (137 mg).

Analysis: HPLC-MS: R_(t)=0.44 min (X012_S01), M+H=474

Step 2: To 5.2 (61 mg) and Cs₂CO₃ (93 mg) was added 11.1 (68 mg)dissolved in DMF (1 mL) and the suspension was heated to 70° C. for 3 h.Additional 5.2 (45 mg) and Cs₂CO₃ (93 mg) was added and stirringcontinued for 5 h at 70° C., then further 5.2 (45 mg) and Cs₂CO₃ (93 mg)was added and stirring continued at 80° C. for 10 h and 3 days atambient temperature. The mixture was diluted with DCM (20 mL) and water(20 mL) and the phases were separated. The water phase was extractedwith DCM (20 mL) and the combined organic phases were dried,concentrated and purified via prep HPLC to provide 10.2 (57 mg) ascolorless oil.

Analysis: HPLC-MS: R_(t)=0.65 min (X012_S01), M+H=586

Step 3: To 10.2 (57 mg) was added trifluoracetic acid (2 mL) and themixture was stirred for 3 h at 80° C. The mixture was concentrated andpurified via prep HPLC to provide Example 9 (23.7 mg)

Analysis: HPLC-MS: R_(t)=0.90 min (003_CA03), M+H=452

Synthesis of4-(1-{6-[(R)-(3S,3aR,7aR)-1-(Hexahydro-furo[3,2-b]pyran-3-yl)-1H-pyrazol-4-yl]-2,3-dimethyl-2H-indazol-4-yloxy}-ethyl)-pyrrolidin-2-one(Example 10)

Step 1: To 5.1 (64 mg) and Cs₂CO₃ (93 mg) was added 11.1 (68 mg)dissolved in DMF (1 mL) and the suspension was heated to 70° C. for 3 h.Additional 5.1 (45 mg) and Cs₂CO₃ (93 mg) was added and stirringcontinued for 5 h at 70° C., then further 5.1 (45 mg) and Cs₂CO₃ (93 mg)was added and stirring continued at 80° C. for 10 h and 3 days atambient temperature and 3 h at 100° C. The mixture was diluted with DCM(20 mL) and water (20 mL) and the phases were separated. The water phasewas extracted with DCM (20 mL) and the combined organic phases weredried, concentrated and purified via prep HPLC to provide 10.3 (42 mg)as colorless oil.

Analysis: HPLC-MS: R_(t)=0.64 min (X012_S01), M+H=600

Step 2: To 10.3 (41 mg) was added trifluoracetic acid (2 mL) and themixture was stirred for 3 h at 80° C. The mixture was concentrated andpurified via prep HPLC to provide Example 10 (17.1 mg).

Analysis: HPLC-MS: R_(t)=0.88 min (003_CA03), M+H=466

Synthesis of(R)-4-((R)-1-{6-[1-(2-Fluoro-ethyl)-1H-pyrazol-4-yl]-2,3-dimethyl-2H-indazol-4-yloxy}-ethyl)-pyrrolidin-2-one(Example 11)

To 9.1 (150 mg), 3.6 (35 mg) andDicyclohexyl-[2-(2,4,6-triisopropylphen-yl)phenyl]phosphane[2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium (17 mg) in dioxan(1 mL) and 2M aqueous Na₂CO₃ (394 μL) was heated for 3 h mins at 100° C.Water was added and the water phase was extracted 3× with DCM and thecombined organic phases concentrated, dissolved in MeOH and filtered viaAgilent StratoSpheres PL-Thiol MP SPE and concentrated to provide 10.4which was used without further purification for the next step.

Analysis: HPLC-MS: R_(t)=0.53 min (X011_S03), M+H=520

Step 2: To 10.4 (107 mg) was added trifluoracetic acid (1.5 mL) andheated for 2.5 h at 70° C. To the mixture was added water and sataqueous NaHCO₃ and the water phase was extracted 2× with DCM. Thecombined organic phases were concentrated and purified via prep HPLC toprovide Example 11 (12 mg) as white solid.

Analysis: HPLC-MS: R_(t)=0.41 min (X011_S03), M+H=386

¹H NMR (DMSO, 400 MHz) δ 1.32 (3H, d, J=6.0 Hz), 2.19-2.37 (2H, m), 2.63(3H, s), 2.75-2.84 (1H, m), 3.11-3.15 (1H, m), 3.40 (1H, t, J=9.1 Hz),3.94 (3H, s), 4.40 (1H, t, J=4.7 Hz), 4.47 (1H, t, J=4.7 Hz), 4.73-4.78(2H, m), 4.86 (1H, t, J=4.7 Hz), 6.56 (1H, s), 7.20 (1H, s), 7.56 (1H,s), 7.96 (1H, s), 8.23 (1H, s)

The following Examples were synthesized in analogous manner to Example11 using intermediate 9.1 and one of the following palladium catalystsystems:

Bromide (corresponding Yield Example to formula 3) A) or B) AnalysisExample 16 4-Bromo-1- 27 mg HPLC-MS: (R)-4-((R)-1-{2,3- (2,2,5,5- (41%)R_(t) = 0.70 min (003_ Dimethyl-6-[1- tetramethyl- (two CA04), M + H =466 (2,2,5,5-tetramethyl- tetrahydro- steps) ¹H NMR (DMSO, 400tetrahydro-furan-3- furan- B) MHz) δ 0.77 (3H, d, yl)-1H-pyrazol-4-yl]3-yl)-1H- J = 1.1 Hz), 1.27 2H-indazol-4-yloxy}- pyrazole 3.2 (3H, s),1.33 (3H, ethyl)-pyrrolidin-2- d, J = 6.0 Hz), 1.37 one (6H, s),2.20-2.38 (3H, m), 2.64 (3H, s), 2.76-2.85 (2H, m), 3.11-3.15 (1H, m),3.38-3.42 (1H, m), 3.95 (3H, s), 4.74-4.81 (2H, m), 6.66 (1H, s), 7.24(1H, s), 7.56 (1H, s), 7.97 (1H, s), 8.34 (1H, d, J = 4.0 Hz) Example 172-(4-Bromo- 6 mg HPLC-MS: 2-(4-{2,3-Dimethyl- pyrazol-1-yl)- (9%) R_(t)= 0.41 min 4-[(R)-1-((R)-5-oxo- 2-methyl- (two (X012_S01),pyrrolidin-3-yl)- propionitrile 3.3 steps) M + H = 407ethoxy]-2H-indazol- A) 6-yl}-pyrazol-1-yl)-2- methyl-propionitrileExample 22 4-Bromo-1-(3, 80 mg HPLC-MS: (R)-4-((R)-1-{6-[1- 3-difluoro-(35%) R_(t) = 0.592 min (3,3-Difluoro- cyclopentyl)- B) (X018_S03), M +cyclopentyl)-1H- 1H-pyrazole 3.4 H = 444 pyrazol-4-yl]-2,3-dimethyl-2H-indazol- 4-yloxy}-ethyl)- pyrrolidin-2-one A)1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) or B)Dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane[2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium

Synthesis of(R)-4-((R)-1-{3-Fluoro-2-methyl-6-[1-(3,3,3-trifluoro-propyl)-1H-pyrazol-4-yl]-2H-indazol-4-yloxy}-ethyl)-pyrrolidin-2-one(Example 12)

To 12.1 (40 mg), 3.5 (19 mg) and1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (2.9 mg) indioxane (1 mL) and 2M aqueous Na₂CO₃ (119 μL) was heated over night at45° C. The mixture was diluted with MeOH and filtered via AgilentStratoSpheres PL-Thiol MP SPE, concentrated and purified via prep HPLCto provide Example 12 (8 mg).

Analysis: HPLC-MS: R_(t)=0.48 min (X011_S03), M+H=440

¹H NMR (DMSO, 400 MHz) b 1.31 (3H, d, J=6.1 Hz), 2.17-2.32 (2H, m),2.71-2.81 (1H, m), 2.85-2.98 (2H, m), 3.09-3.13 (1H, m), 3.37 (1H, t,J=901 Hz), 3.92 (3H, d, J=1.2 Hz), 4.39 (2H, t, J=6.9 Hz), 4.70-4.76(1H, m), 6.63 (1H, s), 7.17 (1H, s), 7.53 (1H, s), 8.00 (1H, s), 8.32(1H, s)

The following Example 14 was synthesized in analogous manner to Example12

Bromide (corresponding to Example formula 3) Yield Analysis Example 144-Bromo-1- 22 mg HPLC-MS: (R)-4-((R)-1-{3-Fluoro-2- (2,2,5,5- (24%)R_(t) = 0.54 min methyl-6-[1-(2,2,5,5- tetramethyl- (X011_S03),tetramethyl-tetrahydro-furan-3- tetrahydro-furan-3- M + H = 470yl)-1H-pyrazol-4-yl]-2H- yl)-1H-pyrazole 3.2 indazol-4-yloxy}-ethyl)-pyrrolidin-2-one

4.5 Analytical Methods

The Example compounds prepared according to the foregoing synthesisschemes were characterised by the following chromatographic methodsand/or NMR spectroscopy.

4.5.1 Chromatographic Methods (HPLC-MS Methods)

Method A

Column: Xbridge BEH C18, 2.1 × 30 mm, 1.7 μm Column supplier: WatersGradient/ % Sol Solvent [H₂O, % Sol Flow Temp Time [min] 0.1% NH₃][Acetonitril] [ml/min] [°C.] 0.00 99  1 1.3 60 0.02 99  1 1.3 60 1.00  0100 1.3 60 1.10  0 100 1.3 60

Method B:

Column: Sunfire C18, 3 × 30 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol [H₂O, % Sol Flow Temp Time [min] 0.1% TFA][Methanol] [ml/min] [°C.] 0.0  95  5 1.8 60 0.25 95  5 1.8 60 1.70  0100 1.8 60 1.75  0 100 2.5 60 1.90  0 100 2.5 60

Method E:

Column: Sunfire C18, 2.1 × 20 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol [H₂O, % Sol Flow Temp Time [min] 0.10%TFA][Methanol] [ml/min] [° C.] 0.00 99  1 1.3 60 0.15 99  1 1.3 60 1.10  0100 1.3 60 1.25  0 100 1.3 60

Method F:

Column: XBridge C18, 3 × 30 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol [H₂O, % Sol Flow Temp Time [min] 0.1% NH ][Acetonitril] [ml/min] [°C.] 0.00 97  3 2.2 60 0.20 97  3 2.2 60 1.20  0100 2.2 60 1.25  0 100 3 60 1.40  0 100 3 60

Method H:

Eluent A: Hexane

Eluent B: 2-Propanol

Time [min] % A % B Flow rate [mL/min] 00.00 90 10 1.0 20.00 90 10 1.0

The stationary phase used was a Chiralpak AD-H (Daicel), 5 μm;dimension: 150×4.6 mm, (column temperature: constant at 10° C.).Detection DAD 225 nm.

Method I:

Eluent A: Hexane

Eluent B: 2-Propanol

Time [min] % A % B Flow rate [mL/min] 00.00 90 10 1.0 25.00 90 10 1.0

The stationary phase used was a Chiralpak AD-H (Daicel), 5 μm;dimension: 150×4.6 mm, (column temperature: constant at 10° C.).

Detection DAD 225 nm.

Method J:

Column: Sunfire C18, 2.1 × 30 mm, 2.5 μm Column Supplier: Waters % SolGradient/Solvent [H₂O, % Sol Flow Temp Time [min] 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0  99  1 1.5 60 0.02 99  1 1.5 60 1.00 0 100 1.5 60 1.10  0 100 1.5 60Method X018_S03

Column: Sunfire C18, 3.0 × 30 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol [H2O, % Sol Flow Temp Time [min] 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0 95 5 1.5 60 1.3 0 100 1.5 60 1.5 0 1001.5 60Method X018_S01

Column: Sunfire C18, 2.1 × 30 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol [H2O, % Sol Flow Temp Time [min] 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0  99 1 1.5 60 0.02 99 1 1.5 60 1.00 0100 1.5 60 1.10 0 100 1.5 60Method X011_S03

Säule: Xbridge BEH C18, 2.1 × 30 mm, 1.7 μm Säulen-Hersteller: WatersVerlauf/Löslichkeit % Sol [H2O, % Sol Flow Temp Zeit [min] 0.1% NH3][Acetonitril] [ml/min] [° C.] 0.00 95 5 1.3 60 0.02 95 5 1.3 60 1.00 0100 1.3 60 1.10 0 100 1.3 60Method X012_S01

Method Name: X012_S01 Method Name: X012_S01 Column: Xbridge BEH C18, 2.1× 30 mm, 1.7 μm Column Supplier: Waters Gradient/Solvent % Sol [H2O, %Sol Flow Temp Time [min] 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.0  991 1.6 60 0.02 99 1 1.6 60 1.00 0 100 1.6 60 1.10 0 100 1.6 60Method X012_S02

Method Name: X012_S02 Column: Xbridge BEH C18, 2.1 × 30 mm, 1.7 μmColumn Supplier: Waters Gradient/Solvent % Sol [H2O, % Sol Flow TempTime [min] 0.1% TFA] [Acetonitril] [ml/min] [° C.] 0.0  99 1 1.3 60 0.0299 1 1.3 60 1.00 0 100 1.3 60 1.10 0 100 1.3 60Method X016_S01

Method Name: X016_S01 Column: Xbridge BEH Phenyl, 2.1 × 30 mm, 1.7 μmMethod Name: X016_S01 Column Supplier: Waters Gradient/Solvent % Sol[H2O, % Sol Flow Temp Time [min] 0.1% TFA] [Acetonitril] [ml/min] [° C.]0.0  99 1 1.6 60 0.02 99 1 1.6 60 1.00 0 100 1.6 60 1.10 0 100 1.6 60Method X017_S01

Column: Zorbax Stable Bond C18, 2.1 × 30 mm, 1.8 μm Column Supplier:Waters Gradient/Solvent % Sol [H2O, % Sol Flow Temp Time [min] 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0  99 1 1.6 60 0.02 99 1 1.6 60 1.00 0100 1.6 60 1.10 0 100 1.6 60

Method P:

Column: Supelco Ascentis Express (2.1×30 mm, 2.7 μm column)

Flow rate: 1 ml/min

Solvent A: 0.1% Formic acid/water

Solvent B: 0.1% Formic acid/acetonitrile

Injection volume: 3 μL

Column temperature: 40° C.

UV Detection wavelength: 215 nm

Eluent: 0 to 1.5 minutes, constant gradient from 95% solvent A+5%solvent B to 100% solvent B; 1.5 to 1.6 minutes, 100% solvent B; 1.60 to1.61 minutes, constant gradient from 100% solvent B to 95% solvent A+5%solvent B; 1.61 to 2.00 minutes, 95% solvent A+5% solvent B.

MS detection using Waters LCT Premier, QTof micro, ZQ or ShimadzuLCMS2010EV UV detection using Waters 2996 photodiode array, Waters 2998photodiode array, Waters 2487 UV or Shimadzu SPD-M20A PDA

Method 001_CA02

Column: SunFire C18_3.0 × 30 mm, 2.5 μm Column Supplier: WatersDescription: Waters Acquity, QDa Detector Gradient/Solvent % Sol[Acetonitrile Flow Temp Time [min] 0.08% TFA] [ml/min] [° C.] 0.0 5.01.5 40.0 1.3 100.0 1.5 40.0 1.5 100.0 1.5 40.0 1.6 5.0 1.5 40.0Method 003_CA03

Device description: Agilent 1100 with DAD, CTC Autosampler and WatersMS-Detector Column: Sunfire C18_3.0 × 30 mm_3.5 μm Column producer:Waters Description: Gradient/Solvent % Sol [H2O % Sol Flow Temp Time[min] 0.1% TFA] [Acetonitrile] [ml/min] [° C.] 0.0 98.0 2.0 2.0 60.0 0.398.0 2.0 2.0 60.0 1.5 0.0 100.0 2.0 60.0 1.6 0.0 100.0 2.0 60.0Method 003_CA04

Device description: Agilent 1100 with DAD, CTC Autosampler and WatersMS-Detector Column: XBridge C18_3.0 × 30 mm, 2.5 μm Column producer:Waters Gradient/Solvent % Sol [H2O % Sol Flow Temp Time [min] 0.1%NH4OH] [Acetonitrile] [ml/min] [° C.] 0.0 98.0 2.0 2.0 60.0 1.2 0.0100.0 2.0 60.0 1.4 0.0 100.0 2.0 60.0Method Z001_005

Column: XBridge C18, 3 × 30 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol [H2O, % Sol Flow Temp Time [min] 0.1% TFA][Methanol] [ml/min] [° C.] 0.0  95 5 1.9 60 0.20 95 5 1.9 60 1.55 0 1001.9 60 1.60 0 100 2.4 60 1.80 0 100 2.4 60Method Z018_S03

Column: Sunfire, 3 × 30 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol [H2O, % Sol Flow Temp Time [min] 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0  95 5 1.9 60 0.20 95 5 1.9 60 1.55 0100 1.9 60 1.60 0 100 2.4 60 1.80 0 100 2.4 60Method Z018_S04

Column: Sunfire, 3 × 30 mm, 2.5 μm Column Supplier: WatersGradient/Solvent % Sol [H2O, % Sol Flow Temp Time [min] 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60Method V011_S01

Column: XBridge C18, 4.6 × 30 mm, 3.5 μm Column Supplier: WatersGradient/Solvent % Sol [H2O, % Sol Flow Temp Time [min] 0.1% NH3] [ACN][ml/min] [° C.] 0.0 97 3 5 60 0.2 97 3 5 60 1.6 0 100 5 60 1.7 0 100 560Method X018_S02

Method Name: Column: Sunfire C18, 2.1 × 30 mm, 2.5 μm Column Supplier:Waters Gradient/Solvent % Sol [H2O, % Sol Flow Temp Time [min] 0.1% TFA][Acetonitril] [ml/min] [° C.] 0.0  99 1 1.3 60 0.02 99 1 1.3 60 1.00 0100 1.3 60 1.10 0 100 1.3 60

Method G:

Eluent A: Water/0.2% KH₂PO₄ pH=3

Eluent B: Acetonitrile

Time [min] % A % B Flow rate [mL/min] 0.00 80 20 1.50 5.00 20 80 1.508.00 20 80 1.50

The stationary phase used was a Inertsil C8-3 (GL Sciences), 5 μm;dimension: 100×4.0 mm,

(column temperature: constant at 30° C.). Detection UV 220 nm.

4.5.2 NMR Spectroscopy

Configuration of the Bruker DRX 500 MHz NMR

High performance digital NMR spectrometer, 2-channel microbay consoleand Windows XP host workstation running Topspin version 1.3.

Equipped with:

-   -   Oxford instruments magnet 11.74 Tesla (500 MHz proton resonance        frequency)    -   B-VT 3000 temperature controller    -   GRASP II gradient spectroscopy accessory for fast acquisition of        2D pulse sequences    -   Deuterium lock switch for gradient shimming    -   5 mm Broad Band Inverse geometry double resonance probe with        automated tuning and matching (BBI ATMA). Allows ¹H observation        with pulsing/decoupling of nuclei in the frequency range ¹⁵N and        ³¹P with ²H lock and shielded z-gradient coils.

Configuration of the Bruker DPX 400 MHz NMR

High performance one bay Bruker 400 MHz digital two channel NMRspectrometer console and Windows XP host workstation running XwinNMRversion 3.5.

-   -   Equipped with:    -   Oxford instruments magnet 9.39 Tesla (400 MHz proton resonance        frequency)    -   B-VT 3300 variable temperature controller unit    -   Four nucleus (QNP) switchable probe for observation of ¹H, ¹³C,        ¹⁹F and ³¹P with ²H lock

Configuration of the Bruker 500 MHz NMR

High performance digital NMR spectrometer, 2-channel one bay console andLinux host workstation running Topspin version 2.1 PL6.

Equipped with:

-   -   Bruker-Biospin AVANCE III 500A magnet 11.75 Tesla (500 MHz        proton resonance frequency)    -   B-VT 3000 temperature controller    -   5 mm Multinuclear Broad Band fluorine observe (BBFO) probe with        digital tuning covering the range from ¹⁵N and ³¹P as well as        ¹⁹F with ¹H decoupling.

Configuration of the Bruker DPX 400 MHz NMR

High performance digital NMR spectrometer, 2-channel microbay consoleand Linux host workstation running Topspin version 2.1 PL6

Equipped with:

-   -   Bruker-Biospin AVANCE III DPX400C magnet 9.40 Tesla (400 MHz        proton resonance frequency)    -   B-VT 3200 variable temperature controller unit

5 mm Multinuclear Broad Band fluorine observe (BBFO) probe with digitaltuning covering the range from ¹⁵N and ³¹P as well as ¹⁹F with ¹Hdecoupling.

5. EXAMPLES

The following Examples were prepared analogously to the methods ofsynthesis described above. These compounds are suitable as SYKinhibitors and have IC₅₀-values with regard to SYK-inhibition of lessthan 10 nMol in the SYK inhibition assay and EC₅₀-values of less than150 nMol in the CD63-assay. Additionally these compounds exhibit a verygood SYK-selectivity which means that—whereas SYK is inhibitedeffectively—other kinases such as Aurora B (AURB), FLT3, GSK3β, etc. arenot or almost not inhibited at all (further kinases which should not beeffectively inhibited are RET, FLT4 RPS6KA3, STK22D and EPHA2).Consequently undesired side effects of these effective SYK-inhibitors ofthe invention are minimized.

AURB phosphorylates Ser10 and Ser28 on histone H3, a key event inmitosis and cellular proliferation. Inhibition of AURB therefore has thepotential to block cellular proliferation, and could compromise tissuesthat exhibit a high cellular turnover, such as the intestine or the bonemarrow. It is therefore desired to avoid parallel AURB inhibition of aneffective SYK inhibitor to improve the overall clinical safety profileof the compound. Consequently all example compounds show IC₅₀-valueswith regard to Aurora B inhibition of more than 10000 nMol and theIC_(50(AURB))/IC_(50 (SYK))-ratios of all example compounds are morethan 10000, preferably even more than 15000.

FLT3 is a tyrosine kinase receptor. When an FLT3 ligand binds to thereceptor, the intrinsic tyrosine kinase activity of the receptor isactivated, which in turn phosphorylates and activates signaltransduction molecules (such as SHC) which in turn propagates the signalin the cell. Signaling through FLT3 plays a role in cell survival,proliferation, and differentiation and is important for lymphocyte (Bcell and T cell) development. It is therefore desired to avoid parallelFLT3 inhibition of an effective SYK inhibitor to improve the overallclinical safety profile of the compound. Consequently all examplecompounds of the instant invention show IC₅₀-values with regard to FLT3inhibition of more than 1000 nMol.

Glycogen synthase kinase 3 beta (GSK3β) is a proline-directedserine-threonine kinase that is prominent in the TGF- and Wntintracellular signalling pathways. GSK3β facilitates a number ofintracellular signalling pathways including the activation of β-catenincomplex. In adults, GSK3β is involved in cellular proliferation andenergy metabolism, whilst in neonates is involved in neuronal celldevelopment and body pattern formation. It is therefore desired to avoidparallel GSK3β inhibition of an effective SYK inhibitor to improve theoverall clinical safety profile of the compound. Consequently allexample compounds of the invention show IC₅₀-values with regard to GSK3βinhibition of more than 5000 nMol, preferably of more than 10000 nMol.

The IC₅₀-values with respect to SYK-inhibition, with respect to Aurora Band FLT3-inhibition for each of the individual example substances areshown in the following Table 1 and were experimentally determined asfollows:

5.1 SYK Kinase Inhibition Test

Recombinant human SYK (amino acids 342-635) was expressed as a fusionprotein with an N-terminal GST tag, affinity-purified and deep-frozen ata concentration of approx. 50-100 μM in storage buffer (25 mM HEPESpH7.5; 25 mM MgCl₂; 5 mM MnCl₂; 50 mM KCl; 0.2% BSA; 0.01% CHAPS; 100 μMNa₃VO₄; 0.5 mM DTT, 10% glycerol) at −80° C. until use.

The catalytic activity of the GST-SYK kinase fusion protein wasdetermined using the Kinase Glo® Luminescence Kinase test (Promega;V6712). In this homogeneous test the amount of ATP remaining after thekinase reaction is quantified by a luciferin-luciferase reaction usingluminescence. The luminescence signal obtained correlates with theamount of ATP still present and thus correlates inversely with theactivity of the kinase.

Method

The test compounds were dissolved in 100% DMSO at a concentration of 10mM and diluted in DMSO to a concentration of 1 mM. Serial Dilution isdone in 100% DMSO. All further dilutions of the substances were carriedout with test buffer (25 mM HEPES pH7.5; 25 mM MgCl₂; 5 mM MnCl₂; 50 mMKCl; 0.2% HSA; 0.01% CHAPS; 100 μM Na₃VO₄; 0.5 mM DTT). Dilution stepsand concentration range were adapted according to need. 7 μl aliquots ofthese dilutions were transferred into a 384-well Optiplate (PerkinElmer, #6007290). GST-SYK was diluted to 12 nM in the test buffer and 5μl of this dilution were used in the kinase test (final concentration ofSYK=4 nM in a total volume of 15 μl). After 15 minutes incubation atroom temperature 3 μl of a mixture of 750 nM ATP and 100 μg/ml poly(L-Glutamic acid L-Tyrosine 4:1), Fluka #81357) in test buffer wereadded to each well and the incubation was continued for a further 60minutes at room temperature.

Positive controls are the reaction mixtures that contain no testsubstance; negative controls (blanks) are reaction mixtures that containno kinase.

After 60 minutes, 10 μl Kinase-Glo® solution (Promega, Cat. # V6712)(heated to room temperature) were added to each well and incubation wascontinued for a further 15 minutes. The plates were read in EnvisionLuminescence Reader (Perkin-Elmer).

Data Evaluation and Calculation:

The output file of the reader is a csv file that contains the wellnumber and measured relative light units (RLU). For data evaluation andcalculation, the measurement of the negative control was set as 100%ctrl and the measurement of the positive control was set as 0% ctrl.Based on this values the % value for the measurement of each substanceconcentration was calculated using an Assay Explorer software(Accelrys). Normally, the % ctrl values calculated are between 0% and100% values but may also occur outside these limits in individual casesbased on variability or compound characteristics. The IC₅₀-values werecalculated from the % ctrl values using Assay Explorer software.Calculation: [y=(a−d)/(1+(x/c)^b)+d] a=low value, d=high value; x=concM; c=IC50 M; b=hill; y=% ctrl.

Satisfying SYK inhibitory capacities are represented by anIC_(50(SYK))-Value measured by this assay of <10 nMol.

5.2 CD63-Assay (Cellular Assay for SYK-Inhibition)

SYK is essential for the FcεR1-mediated activation and degranulation ofmast cells and basophils. In this assay, IgE raised againstdinitrophenol (DNP) is incubated in whole blood where it binds to theFcεR1 on basophils. Subsequently the antigen DNP is added, which bindsto the FcεR1-bound IgE, resulting in SYK dependent basophildegranulation. CD63 normally resides on the intracellular granulemembrane within basophils, which upon degranulation, is then expressedon the surface where it can be detected by flow cytometry. Surfaceexpression of CD63 correlates extremely well with the release ofhistamine from basophils. The CD63 assay has previously been validatedas a clinical target engagement biomarker in the Fostamatinib SYKprogram (Braselmann et al, J. Pharm. Exp. Therap. 319:998-1008, 2006).

Method:

Heparinized whole blood is mixed gently (vortex mixer) and 1001 μL pertest aliquoted into a 96 well plate. Anti-DNP (1 mg/ml) is diluted 1:100with PBS/0.1% HSA to 10 μg/ml (final concentration: 1 μg/mL). Pre-diluteDNP/BSA (5 mg/ml) to a concentration of 60 ng/ml with washing solution.

Compounds: Solutions of 1 mM; 100 μM; 10 μM; 1 μM and 0.11 μM areprepared with 100% DMSO. 1:100 dilutions with PBS/0.1% HSA to generateconcentrations of 10 μM; 1 μM; 0.1 μM; 0.01 μM; 0.001 μM (finalconcentration: 1000; 100; 10; 1; 0.1 nM).

Reagents are provided from the Basotest® kit.

Incubate 10 μl of 10 μg/ml anti DNP and 10 μl of compound with 100 μlwhole blood in a 37° C. pre-warmed water bath. After 30 minutes, 20 μlof STIMULATION BUFFER is added to the whole blood samples and vortexedgently. Incubate the samples for 10 min at 37° C. in a water bath. 100μl of DNP/BSA is added per test to the whole blood. Add 100 μl of theWASHING SOLUTION to a further test tube as a negative control. Add 100μl of DNP/BSA (final 30 ng/ml) in the compound tubes. All tubes aremixed once more. The samples are incubated for 20 min at 37° C. in awater bath.

Stop degranulation by incubating the samples on ice for 5 min. Add 20 μlof STAINING REAGENT to each tube. Vortex and incubate the tubes for 20min in an ice bath, covered to prevent exposure to light. The wholeblood samples are lysed and fixed with 2 ml of pre-warmed (roomtemperature) 1×LYSING SOLUTION. Vortex and incubate for 10 min at roomtemperature. Spin down cells (5 min, 250×g, 4° C.). Discard thesupernatant.

Add 3 ml of WASHING SOLUTION to the tubes. Centrifuge the tubes (5 min,250×g, 4° C.). Aspirate the supernatant. Add 200 μl WASHING SOLUTION tothe cell pellet, vortex.

Incubate the tubes in a covered ice bath until analysis.

Cells are analysed by flow cytometry using the blue-green excitationlight (488 nm argon-ion laser). Acquire data by using fluorescencetriggering in the FL2 channel (PE) to gate on basophilic granulocytesexpressing high amounts of IgE. This live gating reduces the amount ofdata and saves memory capacity. Acquire at least 500 basophils persample.

Data Evaluation and Calculation:

For data evaluation and calculation, the measurement of the negativecontrol (unstimulated blood) was set as 100% control and the measurementof the positive control (DNP/anti-DNP stimulated blood) was set as 0%control. Based on these values the % value for the measurement of eachsubstance concentration was calculated, a concentration-effect curvefitted and an EC₅₀ value calculated using GraphPad Prism version 6.01for Windows. The EC₅₀ value was calculated using a nonlinear fitting(log(inhibitor) vs. response—variable slope). Normally, the % controlvalues calculated are between 0% and 100% values but may also occuroutside these limits in individual cases based on variability orcompound characteristics.

Satisfying CD63 inhibitory capacities are represented by an EC₅₀-valuemeasured by this assay of <150 nMol.

5.3 Aurora B Kinase Test

Recombinant human Aurora B (amino acids 1-344, clone number DU1773,Molecular weight 40.2 kDa, University of Dundee) was expressed as afusion protein with an N-terminal His tag, affinity-purified anddeep-frozen at a concentration of approx. 0.25-0.5 mg/ml in storagebuffer (50 mM Tris-HCl pH 8; 25 mM Na—ß-glycerophosphat; 0.1 mM EGTA;150 mM NaCl; 0.03% Brij-35; 1 mM DTT and 10% glycerol) at −80° C. untiluse.

The activity of the Aurora B kinase protein was determined using the ADPGlo® Luminescence Kinase test (Promega; V9103X). In this homogeneoustest the amount of ADP remaining after the kinase reaction is quantifiedby a luciferin-luciferase reaction using luminescence. The luminescencesignal obtained correlates with the amount of ADP still present and thuscorrelates with the activity of the protein kinase.

Method

The test compounds were dissolved in 100% DMSO at a concentration of 10mM and diluted in DMSO to a concentration of 5 mM. Serial Dilution isdone in 1:10 steps in 100% DMSO. All further dilutions of the substanceswere carried out with test buffer (50 mM Hepes, pH 7.5, 10 mM MgCl2, 1mM EGTA, 60 μM Ultra Pure ATP, 0.01% Brij35, 0.1% BSA, 5 mM8-Glycerophosphate) until a concentration was reached which was 2.5times above the final test concentration (final concentration of thecompounds: 50 μM to 0.005 nM). 4 μl aliquots of these dilutions weretransferred into a 384-well Optiplate (Perkin Elmer, #6007290).His-Aurora B was diluted to 125 nM in the test buffer and 4 μl of thisdilution were used in the kinase test (final concentration of AuroraB=50 nM in a total volume of 10 μl). After 15 minutes incubation at roomtemperature 2 μl of 250 μM substrate ([LRRLSLGLRRLSLGLRRLSLGLRRLSLG];University of Dundee) in test buffer were added to each well and theincubation was continued for a further 60 minutes at room temperature.

Positive controls are the reaction mixtures that contain no testsubstance; negative controls (blanks) are reaction mixtures that containno kinase.

After 60 minutes, 10 μl ADP-Glo® solution (ADP-Glo Reagent #V912BPromega) (heated to room temperature) were added to each well andincubation was continued for a further 40. minutes. Then 20 μl Kinasedetection mix (Detection Buffer #V913B Promega; Kinase DetectionSubstrate #V914B Promega) were added and incubated for 40 minutes atroom temperature. The plates were read in Envision Luminescence Reader(Perkin-Elmer).

Data Evaluation and Calculation:

The output file of the reader is a csv file that contains the wellnumber and measured RLU. For data evaluation and calculation, themeasurement of the negative control was set as 0% ctrl and themeasurement of the positive control was set as 100% ctrl. Based on thisvalues the % value for the measurement of each substance concentrationcan be calculated using an Assay Explorer software (e.g. Accelrys).Normally, the % ctrl values calculated are between 0% and 100% valuesbut may also occur outside these limits in individual cases based onvariability or compound characteristics. The IC₅₀-values were calculatedfrom the % ctrl values using Assay Explorer software. Calculation:[y=(a−d)/(1+(x/c)^b)+d], a=low value, d=high value; x=conc M; c=IC50 M;b=hill; y=% ctrl.

The compounds of the instant invention are SYK-inhibitors and should notaffect other kinases such as AURB which is generally reflected by alarge IC_(50(AURB))-Value, preferably of >10000 nMol and more preferablyof >15000 nMol, particularly preferably of >20000 nMol and by a ratioIC_(50(AURB))/IC_(50(SYK))>10000, more preferably >15000, particularlypreferable >20000.

5.4 FLT3 Kinase Test

Recombinant human FLT3 (amino acids 564-958, Molecular weight 48.6 kDa,Invitrogen #PR4666C) was expressed with an Histidine tag,affinity-purified and deep-frozen at a concentration of approx. 0.35mg/ml in storage buffer (50 mM Tris (pH 7.5), 100 mM NaCl, 0.05 mM EDTA,0.05% NP-40, 2 mM DTT and 50% Glycerol) at −80° C. until use. Theactivity of the FLT3 kinase protein was determined using the ADP Glo®Luminescence Kinase test (Promega; V9103X). In this homogeneous test theamount of ADP remaining after the kinase reaction is quantified by aluciferin-luciferase reaction using luminescence. The luminescencesignal obtained correlates with the amount of ADP still present and thuscorrelates with the activity of the protein kinase.

Method

The test compounds were dissolved in 100% DMSO at a concentration of 10mM and diluted in DMSO to a concentration of 5 mM. Serial Dilution isdone in 1:10 steps in 100% DMSO. All further dilutions of the substanceswere carried out with test buffer (50 mM Hepes, pH 7.5, 10 mM MgCl2, 1mM EGTA, 0.01% Brij35, 0.1% BSA) until a concentration was reached whichwas 2.5 times above the final test concentration (final concentration ofthe compounds: 50 μM to 0.005 nM). 4 μl aliquots of these dilutions weretransferred into a 384-well Optiplate (Perkin Elmer, #6007290). FLT3enzyme was diluted to 5 nM in the test buffer and 4 μl of this dilutionwere used in the kinase test (final concentration of FLT3=2 nM in atotal volume of 10 μl). After 60 minutes incubation at room temperature2 μl mixture of 2.5 mg/ml substrate (Poly-Glu/Tyr; Sigma #P0275) and 2.5mM ultra-pure ATP (Promega #V915B) in test buffer were added to eachwell and the incubation was continued for a further 90 minutes at roomtemperature.

Positive controls are the reaction mixtures that contain no testsubstance; negative controls (blanks) are reaction mixtures that containno kinase.

After 90 minutes, 10 μl ADP-Glo® solution (ADP-Glo Reagent #V912BPromega) (heated to room temperature) were added to each well andincubation was continued for a further 60. minutes. Then 20 μl Kinasedetection mix (Detection Buffer #V913B Promega; Kinase DetectionSubstrate #V914B Promega) were added and incubated for 40 minutes atroom temperature. The plates were read in Envision Luminescence Reader(Perkin-Elmer).

Data Evaluation and Calculation:

The output file of the reader is a csv file that contains the wellnumber and measured RLU. For data evaluation and calculation, themeasurement of the negative control was set as 0% ctrl and themeasurement of the positive control was set as 100% ctrl. Based on thisvalues the % value for the measurement of each substance concentrationcan be calculated using an Assay Explorer software (e.g. Accelrys).Normally, the % ctrl values calculated are between 0% and 100% valuesbut may also occur outside these limits in individual cases based onvariability or compound characteristics. The IC₅₀ values were calculatedfrom the % ctrl values using Assay Explorer software. Calculation:[y=(a−d)/(1+(x/c)^b)+d], a=low value, d=high value; x=conc. M; c=IC50 M;b=hill; y=% ctrl.

The compounds of the instant invention are SYK-inhibitors and should notaffect other kinases such as FLT3 which is generally reflected by alarge IC_(50(FLT3))-value, preferably of >1000 nMol.

5.5 GSK3p Kinase-Test

The inhibition of GSK3beta is measured in ADP-Glo Kinase Assay, Custom,#V9103X, Promega.

Human GSK31 (expressed and purified from SF21 cells) is obtained fromthe University Dundee/Scotland (Dr. James Hastie—Dept. of Biochemistry,51.05 KDa, #899) in 50 mM Tris (pH7.5); 150 mM NaCl; 0.1 mM EGTA, 270 mMSuccrose, 0.1%-mercaptoethanol, 1 mM benzamidine, 0.2 mM PMSF).

The enzyme is diluted to 0.63 mg/ml (12.34 μM), stored in aliquots at−80° C.

Method:

Assay buffer (50 mM Hepes, pH7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Brij35,0.1% BSA) is prepared from stock solutions, which are stored at 4° C.All buffers and reagents are equilibrated to room temperature. Enzymeand ATP are diluted just before use.

Test compounds are dissolved in DMSO to a concentration of 10 mM andstored at −20° C.

Serial dilutions of 10 mM compound stocks are prepared in DMSO with adilution factor of 6.

Compound stocks are used for serial dilution with predilution 1:2 thatresults in a final assay start concentration of 50 μM or other usefulpredilution factors. The final DMSO concentration is 1%.

The serial dilutions (8 concentrations) are transferred to assay bufferwith a dilution of 1:40.

4 μl of these buffer dilutions of compounds are added to 384 welloptiplates (384well plates, optiplate white, flat bottom, #6007290,Perkin Elmer).

Positive and negative controls contain DMSO also diluted 1:40 in assaybuffer, 4 μl/well.

His-GSK3beta is diluted in assay buffer to a concentration 2.5-foldabove final concentration (final=2 nM), 41 μl/well are added to compoundpredilutions and high values. Assay buffer without enzyme is added tonegative controls.

No substrate is needed because of autophosphorylation on enzyme.

Optiplates are centrifuged (short spin), gently shaken, covered with alid and incubated at room temperature for 60 min.

ATP (Ultra Pure ATP, 10 mM #V915B, Promega) is diluted in assay bufferto a concentration 5-fold above final concentration (final=7 M), 2μl/well are added to mixture of compound and enzyme, also to high andlow values.

Optiplates are centrifuged (short spin), gently shaken, covered with alid and incubated at room temperature for 90 min.

10l ADP-Glo Reagent (ADP-Glo Reagent #V912B Promega) is added to allwells to deplate unused ATP. Plates are mixed by gentle shaking,incubation time 60 min, covered with a lid.

20 μl Kinase Detection Reagent (Kinase Detection Substrate #V914BPromega dissolved in Kinase Detection Buffer #V913B Promega) is added toall wells to transform ADP to ATP, which was produced during kinasereaction. Plates are mixed by gentle shaking, incubation time 40 minsealed with top seal, protected from light.

The plates were read in Envision Luminescence Reader (Perkin-Elmer).

Data Evaluation and Calculation:

The output file of the reader is a csv file that contains the wellnumber and measured RLU.

For data evaluation and calculation, the measurement of the negativecontrol was set as 0% ctrl and the measurement of the positive controlwas set as 100% ctrl. Based on this values the % value for themeasurement of each substance concentration can be calculated using anAssay Explorer software (e.g. Accelrys). Normally, the % ctrl valuescalculated are between 0% and 100% values but may also occur outsidethese limits in individual cases based on variability or compoundcharacteristics. The IC₅₀-values were calculated from the % ctrl valuesusing Assay Explorer software. Calculation: [y=(a−d)/(1+(x/c)^b)+d],a=low value, d=high value; x=conc M; c=IC50 M; b=hill; y=% ctrl.

The compounds of the instant invention are SYK-inhibitors and should notaffect other kinases such as GSK31 which is generally reflected by alarge IC_(50(GSK3β))-value, preferably of >5000 nMol and more preferablyof >10000 nMol.

5.6 Human Liver Microsomal Stability Test

Further it is desirable for an SYK-inhibitor that is sufficientlySYK-specific as described above to have certain metabolic stability asmeasured for instance in the presence of human liver microsomescorresponding to Q_(h)<23%, wherein Q_(h) is the percentage of liverblood flow (the stability is better, the lower the Q_(h)-value is). Ifthe Q_(h)-value for the SYK-inhibitor in question is too high (largerthan 23%), it will be difficult to reach an adequate plasma level of thecorresponding SYK— inhibitor in the patient to be treated.

Method:

The metabolic degradation for a specific SYK-inhibitor is performed at37° C. with pooled human liver microsomes (human liver microsomes arecommercially available as “BD UltraPool™” by Corning Life Sciences,Fogostraat 12, 1060 LJ Amsterdam, The Netherlands). The final incubationvolume of 100 μl per time point contains TRIS buffer pH 7.6 at RT (0.1M), magnesium chloride (5 mM), microsomal protein (1 mg/ml) and the testcompound at a final concentration of 1 μM.

Following a short preincubation period at 37° C., the reaction isinitiated by addition of beta-nicotinamide adenine dinucleotidephosphate in its reduced form (NADPH, 1 mM) and terminated bytransferring an aliquot into solvent after different time points.Additionally, the NADPH-independent degradation is monitored inincubations without NADPH, terminated at the last time point.

The quenched (terminated) incubations are then pelleted bycentrifugation (10000 g, 5 min).

An aliquot of the supernatant is assayed by LC-MS/MS for the remainingamount of parent compound. The half-life (t½ INVITRO) is determined bythe slope of the semilogarithmic plot of the concentration-time profile.

Data Evaluation and Calculation:

The intrinsic clearance (CL_INTRINSIC) is calculated by considering theamount of protein in the incubation:CL_INTRINSIC [μl/min/mg protein]=(Ln 2/(t½INVITRO [min]*protein content[mg/ml]))*1000

The protein content [mg/ml] was determined with the “Bicinchoninic AcidKit” of Sigma Aldrich (commercially available).

The upscaled intrinsic Clearance (CL_UP_INT) is calculated byconsidering the liver weight [g liver/kg body weight] and the microsomalrecovery [mg protein/g liver]:CL_UP_INT[ml/min/kg]=0.001*CL_INTRINSIC*liver weight*microsomal recovery

-   -   with microsomal recovery=45 mg protein/g liver    -   with liver weight=25.7 g liver/kg body weight

The percent hepatic blood flow (% O_(h)) is finally calculated byconsidering the human liver blood flow Q [ml/min/kg]:% Q _(h)[%]=((Q*CL_UP_INT)/(Q+CL_UP_INT)/Q)*100

-   -   with liver blood flow (Q)=20.7 ml/min/kg.

5.7 Human Hepatocyte Stability Test

A more comprehensive way to measure the metabolic stability of acompound of the instant invention than microsomal stability (section5.6) is the human hepatocyte stability test as described below. Hereinthe metabolic degradation for the compound in question is performed in ahuman hepatocyte suspension.

Human hepatocytes (typically cryopreserved) are incubated in anappropriate buffer system (e.g. Dulbecco's modified eagle medium plus3.5 μg glucagon/500 mL, 2.5 mg insulin/500 mL and 3.75 mg/500 mLhydrocortison) containing 5% species serum.

Following a (typically) 30 min preincubation in an incubator (37° C.,10% CO₂) 5 μl of the solution of the compound to be tested (80 M; from 2mM in DMSO stock solution diluted 1:25 with medium) are added into 395μl hepatocyte suspension (cell density is in the range of 0.25-5 Miocells/mL, typically 1 Mio cells/mL; the final concentration of thecompound in question is 11 M, the final DMSO concentration is 0.05%).

The cells are incubated for six hours (incubator, orbital shaker) andsamples (25 μl) are taken at 0, 0.5, 1, 2, 4 and 6 hours. Samples aretransferred into acetonitrile and pelleted by centrifugation (5 min).The supernatant is transferred to a new 96-deepwell plate, evaporatedunder nitrogen and resuspended.

The decline of the compound to be tested is analyzed by HPLC-MS/MS.

Data Evaluation and Calculation:

CLint is calculated as followsCL_INTRINSIC=Dose/AUC=(C0/CD)/(AUD+clast/k)×1000/60.

C0: initial concentration in the incubation [μM],

CD: cell density of vital cells [10⁶ cells/mL],

AUD: area under the data [μM×h],

clast: concentration of last data point [μM],

k: slope of the regression line for the compound in question decline[h−1].

The calculated in vitro hepatic intrinsic clearance can be scaled up tothe intrinsic in vivo hepatic Clearance and used to predict hepatic invivo blood clearance (CL) by the use of a liver model (well stirredmodel).CL_INTRINSIC_INVIVO [ml/min/kg]=(CL_INTRINSIC[μL/min/10⁶cells]×hepatocellularity[10⁶ cells/g liver]×liver factor[g/kg bodyweight])/1000CL [ml/min/kg]=CL_INTRINSIC_INVIVO [ml/min/kg]×hepatic blood flow[ml/min/kg]/(CL_INTRINSIC_INVIVO [ml/min/kg]+hepatic blood flow[ml/min/kg])Q _(h)[%]=CL [ml/min/kg]/hepatic blood flow [ml/min/kg])

Hepatocellularity, human: 120×10⁶ cells/g liver

Liver factor, human: 25.7 g/kg bodyweight

Blood flow, human: 21 ml/(min×kg)

A satisfying human hepatocyte stability for a compound in questionmeasured by this assay is represented by a Q_(h)<20% (whereby thestability is better, the lower the Q_(h)-value is).

TABLE 1 Example compounds and their properties with respect toSYK-inhibiton, SYK-selectivity and metabolic stability (asexperimentally determined) SYK AURB FLT3 stability in inhibition CD63assay inhibition inhibition human selectivity IC₅₀-value, EC₅₀-valueIC₅₀-value IC₅₀-value hepatocytes ratio Ex. (chapter 5.1) (chapter 5.2)(chapter 5.3) (chapter 5.4) (chapter 5.7) IC_(50(AURB))/ No. Structure[nM] [nM] [nM] [nM] HEPhu [% Q_(h)] IC_(50(SYK))  1

1  41 34800 2230 10 34800  2

1.3  45 31141 2834 <4 23955  3

2  51 31461 1340 7 15731  4

2.2  64 65200 7410 10 29636  5

3.3  52 50000 3990 <4 15152  6

2.6  42 34100 3730 6 13115  7

1.3  53 26200 2440 <4 20154  8

1.4  47 21112 2071 5 15080  9

1.1  52 23341 1840 6 21219 10

3.3  65 34030 2015 9 10312 11

1.5  65 31200 3480 4 20800 12

2.9  67 29600 5030 <4 10207 13

0.9  58 35984 5219 3 39982 14

3.2  76 50000 4050 12 15625 15

2.2  77 50566 4788 10 22985 16

3.1  82 44400 3490 6 14323 17

2.9  92 50000 11295  4 17241 18

1.1  95 20155 4673 <4 18323 19

1.8 107 23782 4954 7 13212 20

2.5 134 34831 3316 <4 13932 21

1.2  76 17330 2210 7 14442 22

1.2  67 13448 1948 3 11207

TABLE 2 Structurally closest prior art compounds (as disclosed in WO15017610) and their properties regarding SYK-inhibition, SYK-selectivityand metabolic stability (as experimentally determined) SYK AURB FLT3stability in inhibition CD63 assay inhibition inhibition humanselectivity IC₅₀-value EC₅₀-value IC₅₀-value IC₅₀-value hepatocytesratio Prior Art (chapter 5.1) (chapter 5.2) (chapter 5.3) (chapter 5.4)(chapter 5.7) IC_(50(AURB))/ Compound Structure [nM] [nM] [nM] [nM]HEPhu [% Q_(h)] IC_(50(SYK)) example 5.20 on page 506 of WO15017610

0.2 77 162 43 31 810 example 3A.02, on page 196 of WO15017610

1.9 42 1692 384 7 891 example 6.09 on page 559 of WO15017610

0.1 20 37 25 17 370 example 3B.22 on page 219 of WO15017610

0.8 29 771 307 5 964 example 6.60 on page 587 of WO15017610

10.3 483 >50000 6677 <4 >4850

The example compounds of the instant invention No. 1 to 22 (see Table 1)have been synthesized according to Chapter 4 and then the examplecompounds were subjected to the different assays as described in Chapter5 in order to determine

-   -   the capacity of SYK inhibition (low IC₅₀-value stands for a good        SYK-inhibition, in particular IC₅₀-values of <10 nMol in the        “SYK inhibition assay” and ECso-values of <150 nMol in the “CD63        assay” stand for satisfying SYK inhibitory properties)    -   the SYK-selectivity that means a very low inhibition of other        kinases such as for instance        -   a) Aurora B (good SYK-selectivity is reflected by “high”            IC₅₀-values with respect to inhibition of AURB;        -   IC_(50(AURB))>10000 or a ratio of            IC_(50(AURB))/IC_(50(SYK))>10000 nMol is desired and stands            for a good SYK-selectivity),        -   b) FLT3 (good SYK-selectivity is reflected by “high”            IC₅₀-values with respect to inhibition of FLT3,            IC_(50(FLT)3)>1000 nMol is desired and stands for a good            SYK-selectivity),    -   the metabolic stability which can for instance be measured by        the Q_(h)-percentage in human hepatocytes (% Q_(h)<20 stands for        a sufficient metabolic stability for an SYK-inhibitor to be        developed as a medicament).

The structurally closest prior art compounds as disclosed in WO15017610have also been synthesized and were subjected to the same assays asdescribed in Chapter 5 in order to determine the properties of thesestructurally closest prior art compounds with respect to the capacity ofSYK-inhibition, CD63 potency, the SYK-selectivity and the metabolicstability and to compare them to the example compounds of the presentinvention.

Whereas example 5.20 on page 506 of WO15017610, example 3A.02 on page196 of WO15017610, example 6.09 on page 559 of WO15017610 and example3B.22 on page 219 of WO15017610 all have acceptable IC_(50(SYK))-Valueswith an IC_(50(SYK))<10 nMol in the “SYK-inhibition assay” and with anEC₅₀<150 nMol in the “CD63-assay”, these prior art compounds all do notshow a satisfying SYK-selectivity with regard to AURB. The IC_(50(AURB))of these prior art compounds are with 162 nMol, 1692 nMol, 37 nMol and771 nMol significantly smaller than the IC_(50(AURB)) of the examplecompounds of the invention which all have an IC_(50(AURB))>10000 nMol(most of them have even an IC_(50(AURB))>15000 nMol). The same is truefor the ratios IC_(50(AURB))/IC_(50(SYK)) which are for the prior artexamples 5.20, 3A.02, 6.09 and 3B.22 with 810, 891, 370 and 964 allsignificantly lower than 10000. The example compounds of the instantinvention however, have IC_(50(AURB))/IC_(50(SYK)) ratios of >10000,very often even >15000.

Furthermore, example 5.20 on page 506 of WO15017610, example 3A.02 onpage 196 of WO15017610, example 6.09 on page 559 of WO15017610 andexample 3B.22 on page 219 of WO15017610 all do not show a satisfyingSYK-selectivity with regard to FLT3.

The IC_(50(FLT)3) of the prior art compounds example 5.20 on page 506 ofWO15017610, example 3A.02 on page 196 of WO15017610, example 6.09 onpage 559 of WO15017610 and example 3B.22 on page 219 of WO15017610 arewith 43 nMol, 384 nMol, 25 nMol and 307 nMol significantly smaller thanthe IC₅₀(F_(LT3)) of the example compounds of the invention which allhave an IC_(50(FLT)3)>1000 nMol (most of them have even anIC_(50(FLT)3)>2000 nMol).

In contrast to that the prior art compound 6.60 on page 587 ofWO15017610 seems to have with IC_(50(AURB))>50000 nMol and withIC_(50(FLT-3))=6677 nMol at least with respect to the absolutemeasurements a sufficient SYK-selectivity, however for this prior artcompound 6.60 (on page 587 of WO15017610) the SYK inhibitory capacity isnot sufficient with an IC_(50(SYK)) of 10.3 nMol (IC_(50(SYK)) of largerthan 10 nMol) and with an EC_(50(SYK)) in the CD63-assay of 483 nMol(EC₅₀ in the CD63-assay is larger than 150 nMol).

Consequently only the compounds of the instant invention have at thesame time

a) an excellent SYK-inhibitory capacity (IC_(50(SYK))<10 nMol, EC₅₀<150nMol)

b) a good SYK-selectivity (IC_(50(AURB))>10000 nMol, andIC_(50(AURB))/IC_(50(SYK))>10000 and IC_(50(FLT3))>1000 nMol)) and

c) a sufficient metabolic stability (% Q_(h)<20 in human hepatocytes)

which are all properties that are very significant for the use of anSYK-inhibitor as a medicament in order to treat SYK-related diseases.

6. INDICATIONS

As has been found, the compounds of formula 1 or 1′ are characterised bytheir range of applications in the therapeutic field. Particular mentionshould be made of those applications for which the compounds of formula1 or 1′ according to the invention are preferably used on the basis oftheir pharmaceutical activity as SYK-inhibitors. Examples includerespiratory complaints, allergic diseases, osteoporosis,gastrointestinal diseases or complaints, immune or autoimmune diseases,allergic diseases, inflammatory diseases, e.g. inflammatory diseases ofthe joints, skin and eyes and diseases of the peripheral or centralnervous system.

Particular mention should be made of the prevention and treatment ofrespiratory tract and pulmonary diseases which are accompanied byincreased mucus production, inflammation and/or obstructive diseases ofthe airways. Examples of these include asthma, pediatric asthma, ARDS(Adult Respiratory Distress Syndrome), acute, allergic or chronicbronchitis, autoimmune haemolytic anemia, chronic obstructive bronchitis(COPD) (including the treatment of Rhinovirus-induced exacerbations),coughs, allergic rhinitis or sinusitis, allergic rhinoconjunctivitis,chronic rhinitis or sinusitis, alveolitis, farmers' lung, hyperreactiveairways, infectious bronchitis or pneumonitis, bronchiectasis, pulmonaryarterial hypertension, pulmonary fibrosis, bronchial oedema, pulmonaryoedema, pneumonia or interstitial pneumonia triggered by various causessuch as aspiration, inhalation of toxic gases or bronchitis, pneumoniaor interstitial pneumonia triggered by cardiac insufficiency, radiation,chemotherapy, cystic fibrosis or mucoviscidosis, alpha 1-antitrypsindeficiency.

The compounds according to the invention are preferably also suitablefor the treatment of allergic diseases such as for example allergicrhinitis, allergic rhinoconjunctivitis, allergic conjunctivitis, andcontact dermatitis, urticaria/angiooedema and allergic dermatitis.

Mention should also preferably be made of the treatment of inflammatorydiseases of the gastrointestinal tract. Examples of these are Crohn'sdisease and ulcerative colitis.

The compounds according to the invention are preferably also suitablefor the treatment of inflammatory diseases of the joints, of the bloodvessels and of the kidney or inflammatory diseases of the skin and eyes.Examples of these are rheumatoid arthritis, antibody-basedglomerulonephritis, psoriasis, Kawasaki syndrome, coeliac disease(sprue), arteriosclerosis and Wegener's granulomatosis, osteoarthritis,systemic scleroderma, ankylosing spondylitis.

The compounds according to the invention are preferably also suitablefor the treatment of autoimmune diseases. Examples of these arehepatitis (autoimmune-based), lupus erythematodes, lupus nephritis,systemic lupus, Systemic lupus erythematosus, discoid lupus, cutaneouslupus erythematosus (acute, subacute, chronic), anti-phospholipidsyndrome, Berger's disease, Evans's syndrome, immunohaemolytic anaemia,ITP (idiopathic thrombocytopenic purpura; adult, neonatal andpaediatric), myasthenia gravis, Sjögren's syndrome, sclerodermy, Bullouspemphigoid and Pemphigus vulgaris.

The compounds according to the invention are preferably also suitablefor the treatment of B-cell lymphomas, like chronic lymphocyticleukaemia and non-Hodgkin's lymphomas, Waldenstroem macroglubulinemia(Clinical Cancer Research (2015), 21(11), 2538-2545) or T celllymphomas.

The compounds according to the invention are preferably also suitablefor the treatment of Graft-versus-host disease.

Mention may preferably also be made of the prevention and treatment ofdiseases of the peripheral or central nervous system. Examples of theseare acute and chronic multiple sclerosis or non-familial lateralsclerosis.

Mention should also preferably be made of the treatment of systemicsclerosis (SSc). Pamuk Omer Nuri; Can Guray; Ayvaz Suleyman; KaracaTuran; Demirtas Selim; Pamuk Gulsum E; Tsokos George, Clinical andexperimental rheumatology (2015); ISSN: 0392-856X.

Mention should also preferably be made of the treatment of infectiousdiseases. Example of these are malaria (Abstracts, Joint 41st GreatLakes and 46th Central Regional Meeting of the American ChemicalSociety, GrandRapids, Mich., United States, May 27-30 (2015),JGLCRM-283; WO 2014100113) and dengue (Journal of Biological Chemistry,Volume: 290, Issue: 28, Pages: 17306-17320)

Mention may preferably also be made of the prevention and treatment ofosteoporotic diseases such as for example disease-associated osteopenia,osteoporosis and osteolytic diseases.

The present invention relates particularly preferably to the use ofcompounds of formula 1 for preparing a pharmaceutical composition forthe treatment of diseases selected from among asthma, COPD, allergicrhinitis, Adult Respiratory Distress Syndrome, bronchitis, allergicdermatitis, contact dermatitis, ITP, rheumatoid arthritis, systemiclupus erythematosus, lupus nephritis, and allergic rhinoconjunctivitis.

Most preferably, the compounds of formula 1 may be used for thetreatment of a disease selected from among asthma, allergic rhinitis,rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis,allergic dermatitis and COPD.

7. COMBINATIONS

The compounds of formula 1 or 1′ may be used on their own or inconjunction with other active substances of formula 1 or 1′ according tothe invention. The compounds of formula 1 or 1′ may optionally also beused in conjunction with other pharmacologically active substances.Preferably the active substances used here may be selected for examplefrom among the betamimetics, anticholinergics, corticosteroids,PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, MRP4-inhibitors,dopamine agonists, H1-antihistamines, PAF-antagonists, iNos-inhibitos,HMG-CoA reductase inhibitors (statins), PI3-kinase-inhibitors,CCR3-antagonists, CCR2-antagonists, CCR1-antagonists, IKK2-inhibitors,A2a agonists, alpha-4-integrin-inhibitors, CRTH2-antagonists, histamine1, combined H1/H3-antagonists, p38 kinase inhibitors, methylxanthines,ENaC-inhibitors, CXCR1-antagonists, CXCR2-antagonists, ICE-inhibitors,LTB4-antagonists, 5-LO antagonists, FLAP-antagonists. LTB4-antagonists;cromoglycine, dissociated glucocorticoid mimetics, immunesuppressiveagents, cytostatica, non-steroidal anti-inflammatory drugs (NSAIDs),chloroquine, hydroxychloroquine, anti-TNF-antibodies, anti-GM-CSFantibodies, anti-CD46-antibodies, anti-IL-1-antibodies,anti-IL-2-antibodies, anti-IL-4-antibodies, anti-IL-5-antibodies,anti-IL6 antibodies, anti-IL6 receptor antibodies,anti-IL-13-antibodies, anti-IL_18 antibodies, anti-CD30 L antibodies,anti-Ox40L-antibodies, anti-IL-4/IL-13-antibodies, anti-IL-23 (p19)antibodies, anti-IL-12/IL-23 (p40) antibodies, anti-CD3 antibodies,anti-CD4 antibodies, anti-CD154 antibodies, CD89 antibodies, anti-IL-2receptor/CD25 antibodies, anti-CD22 antibodies, anti-interferonantibodies, anti-ICOS antibodies, anti-ICOS antibodies, anti-CD20antibodies, anti-CD40 antibodies, anti-BAFF/BLyS antibodies, anti-CD18antibodies, anti-CD62L antibodies, anti-CD147 antibodies, anti-integrinantibodies, agents interfering with LFA-1, IL-36 pathway modulators,M-CSF/c-fms antagonists, CTLA-4 fusions, mTor modulators, Toll likereceptors 7 inhibitors (TLR7 inhibitor), Toll like receptor 9 inhibitors(TLR9 inhibitors), T cell-costimulatory modulators such as CTLA-4fusions, JAK inhibitors, IRF modulators, CX3 chemokine receptorantagonists (CX3CR1 antagonists), IRAK inhibitors (in particular IRAK1-and IRAK4-inhibitors), Sphingosine-1-phosphate modulators (S1P pathwaymodulators), triple kinase inhibitors against PDGFR, FGFR and VEGFR e.g.Nintedanib or double or triple combinations thereof, such as for examplecombinations of one, two or three compounds selected from among the

-   -   SYK-inhibitors of formula 1 or 1′, betamimetics,        corticosteroids, EGFR-inhibitors and PDE4-antagonists,    -   SYK-inhibitors of formula 1 or 1′, anticholinergics,        betamimetics, corticosteroids, EGFR-inhibitors and        PDE4-antagonists,    -   SYK-inhibitors of formula 1 or 1′, PDE4-inhibitors,        corticosteroids and EGFR-inhibitors,    -   SYK-inhibitors of formula 1 or 1′, EGFR-inhibitors and        PDE4-inhibitors,    -   SYK-inhibitors of formula 1 or 1′ and EGFR-inhibitors,    -   SYK-inhibitors of formula 1, betamimetics and anticholinergics    -   SYK-inhibitors of formula 1 or 1′, anticholinergics,        betamimetics, corticosteroids and PDE4-inhibitors,    -   SYK-inhibitors of formula 1 or 1′, anticholinergics,        betamimetics, corticosteroids, iNOS inhibitors, HMG-CoA        reductase inhibitors.

Combinations of three active substances each taken from one of theabove-mentioned categories of compounds are also an object of theinvention.

Suitable betamimetics used are preferably compounds selected from amongarformoterol, carmoterol, formoterol, indacaterol, salmeterol,albuterole, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol,fenoterol, hexoprenalin, ibuterol, isoetharin, isoprenalin,levosalbutamol, mabuterol, meluadrin, metaproterenol, milveterol,orciprenalin, pirbuterol, procaterol, reproterol, rimiterol, ritodrin,salmefamol, soterenol, sulphonterol, terbutalin, tiaramide, tolubuterol,zinterol,6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazine-3-one;8-{2-[2-(2,4-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;8-{2-[2-(3,5-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;8-{2-[2-(4-Fluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;N-(5-{2-[3-(4,4-Diethyl-2-oxo-4H-benzo[d][1,3]oxazine-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamide;N-(5-{2-[3-(4,4-Diethyl-6-fluoro-2-oxo-4H-benzo[d][1,3]oxazine-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamide;N-(5-{2-[3-(4,4-Diethyl-6-methoxy-2-oxo-4H-benzo[d][1,3]oxazine-1-yl)-,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamide;N-(5-{2-[1,1-Dimethyl-3-(2-oxo-4,4-dipropyl-4H-benzo[d][1,3]oxazine-1-yl)-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methansulfonamide;8-{2-[1,1-Dimethyl-3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;8-{2-[1,1-Dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzoimidazole-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;8-{2-[1,1-Dimethyl-3-(2-oxo-5-trifluormethyl-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;8-{2-[1,1-Dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazine-3-one;N-[2-Hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide;8-Hydroxy-5-((1R)-1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinoline-2-one;8-Hydroxy-5-[(1R)-1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinoline-2-one;5-[(1R)-2-(2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinoline-2-one;[3-(4-{6-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea;4-((1R)-2-{6-[2-(2,6-Dichlor-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol;3-(4-{6-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfonamide;3-(3-{7-[(2R)-2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzenesulfonamide;4-((1R)-2-{6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol,4-(2-{6-[2-(2,6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol;Vilanterol;N-1-Adamantanyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide;2-(3-{2-[2-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-propyl}-phenyl)-N-[4-(4-hydroxy-phenyl)-2-vinyl-penta-2,4-dienyl]-acetamide;(1R)-5-{2-[6-(2,2-Difluor-2-phenyl-ethoxy)-hexylamino]-1-hydroxy-ethyl}-8-hydroxy-1H-quinoline-2-one;(R,S)-4-(2-{[6-(2,2-Difluor-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;(R,S)-4-(2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;(R,S)-4-(2-{[4,4-Difluor-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;(R,S)-4-(2-{[6-(4,4-Difluor-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;(R,S)-5-(2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8-hydroxyquinoline-2(1H)-one;(R,S)-[2-({6-[2,2-Difluor-2-(3-methylphenyl)ethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;4-(1R)-2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;(R,S)-2-(Hydroxymethyl)-4-(1-hydroxy-2-{[4,4,515-tetrafluor-6-(3-phenylpropoxy)-hexyl]amino}ethyl)phenol;(R,S)-[5-(2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2-hydroxyphenyl]formamide;(R,S)-4-[2-({6-[2-(3-Bromophenyl)-2,2-difluoroethoxy]hexyl}amino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;(R,S)—N-[3-(1,1-Difluor-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]-ethyl}amino)hexyl]oxy}ethyl)phenyl]-urea;3-[3-(1,1-Difluor-2-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}ethyl)phenyl]imidazolidine-2,4-dione;(R,S)-4-[2-({6-[2,2-Difluor-2-(3-methoxyphenyl)ethoxy]hexyl}amino)-hydroxyethyl]-2-(hydroxymethyl)phenol;5-((1R)-2-{[6-(2,2-Difluor-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinoline-2(1H)-one;4-((1R)-2-{[4,4-Difluor-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;(R,S)-4-(2-{[6-(3,3-Difluor-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl)-2-(hydroxymethyl)phenol;(R,S)-(2-{[6-(2,2-Difluor-2-phenylethoxy)-4,4-difluorohexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;(R,S)-4-(2-{[6-(2,2-Difluor-3-phenylpropoxy)hexyl]amino}-1-hydroxyethyl)-2-(hydroxymethyl)phenol;3-[2-(3-Chlor-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionamide;N-(2-Diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide;7-[2-(2-{3-[2-(2-Chlor-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one,optionally in the form of the racemates, enantiomers, diastereomers andoptionally in the form of the pharmacologically acceptable acid additionsalts, solvates or hydrates thereof.

According to the invention the acid addition salts of the betamimeticsare preferably selected from among the hydrochloride, hydrobromide,hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably the hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.Of the above-mentioned acid addition salts the salts of hydrochloricacid, methanesulphonic acid, benzoic acid and acetic acid areparticularly preferred according to the invention.

The anticholinergics used are preferably compounds selected from amongtiotropium salts, particularly the bromide salt, oxitropium salts,particularly the bromide salt, flutropium salts, particularly thebromide salt, ipratropium salts, particularly the bromide salt,Aclidinium salts, particularly the bromide salt, glycopyrronium salts,particularly the bromide salt, trospium salts, particularly the chloridesalt, tolterodin,(3R)-1-Phenethyl-3-(9H-xanthene-9-carbonyloxy)-1-azoniabicyclo[2.2.2]octan-salts;2,2-Diphenyl propionic acid tropenole ester-methobromide; 2,2-Diphenylpropionic acid scopine ester-methobromide; 2-Fluor-2,2-Diphenyl aceticacid scopine ester-methobromide; 2-Fluor-2,2-Diphenyl acetic acidtropenole ester-methobromide; 3,3′,4,4′-Tetrafluor benzilic acidtropenole ester-methobromide; 3,3′,4,4′-Tetrafluor benzilic acid scopineester-methobromide; 4,4′-Difluor benzilic acid tropenoleester-methobromide; 4,4′-Difluor benzilic acid scopineester-methobromide; 3,3′-Difluor benzilic acid tropenoleester-methobromide; 3,3′-Difluor benzilic acid scopineester-methobromide; 9-Hydroxy-fluorene-9-carboxylic acid tropenoleester-methobromide; 9-Fluor-fluorene-9-carboxylic acid tropenoleester-methobromide; 9-Hydroxy-fluorene-9-carboxylic acid scopineester-methobromide; 9-Fluor-fluorene-9-carboxylic acid scopineester-methobromide; 9-Methyl-fluorene-9-carboxylic acid tropenoleester-methobromide; 9-Methyl-fluorene-9-carboxylic acid scopineester-methobromide; Benzilic acid cyclopropyl tropineester-methobromide; 2,2-Diphenyl propionic acid cyclopropyltropineester-methobromide; 9-Hydroxy-xanthene-9-carboxylic acidcyclopropyltropine ester-methobromide; 9-Methyl-fluorene-9-carboxylicacid cyclopropyltropine ester-methobromide;9-Methyl-xanthene-9-carboxylic acid cyclopropyltropineester-methobromide; 9-Hydroxy-fluorene-9-carboxilic acidcyclopropyltropine ester-methobromide; 4,4′-Difluor benzilic acid methylester cyclopropyltropine ester-methobromide;9-Hydroxy-xanthene-9-carboxylic acid tropenole ester-methobromide;9-Hydroxy-xanthene-9-carboxylic acid scopine ester-methobromide;9-Methyl-xanthene-9-carboxylic acid tropenole ester-methobromide;9-Methyl-xanthene-9-carboxylic acid scopine ester-methobromide;9-Ethyl-xanthene-9-carboxylic acid tropenole ester-methobromide;9-Difluormethyl-xanthene-9-carboxylic acid tropenole ester-methobromide;9-Hydroxymethyl-xanthene-9-carboxylic acid scopine ester-methobromide;3-[2-(3-Chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionamide;N-(2-Diethylamino-ethyl)-N-{2-[2-(4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide;7-[2-(2-{3-[2-(2-Chloro-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-oneand Darotropium; optionally in the form of the solvates or hydratesthereof.

In the above-mentioned salts the cations tiotropium, oxitropium,flutropium, ipratropium, glycopyrronium, aclidinium and trospium are thepharmacologically active ingredients. As anions, the above-mentionedsalts may preferably contain chloride, bromide, iodide, sulphate,phosphate, methanesulphonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,while chloride, bromide, iodide, sulphate, methanesulphonate orp-toluenesulphonate are preferred as counter-ions. Of all the salts, thechlorides, bromides, iodides and methanesulphonate are particularlypreferred.

Of particular importance is tiotropium bromide. In the case oftiotropium bromide the pharmaceutical combinations according to theinvention preferably contain it in the form of the crystallinetiotropium bromide monohydrate, which is known from WO 02/30928. If thetiotropium bromide is used in anhydrous form in the pharmaceuticalcombinations according to the invention, it is preferable to useanhydrous crystalline tiotropium bromide, which is known from WO03/000265.

Corticosteroids used here are preferably compounds selected from amongbeclomethasone, betamethasone, budesonide, butixocort, ciclesonide,deflazacort, dexamethasone, etiprednole, flunisolide, fluticasone,loteprednole, mometasone, prednisolone, prednisone, rofleponide,triamcinolone, tipredane; Pregna-1,4-diene-3,20-dione,6-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-21-[[4-[(nitrooxy)methyl]benzoyl]oxy]-,(6-alpha,11-beta,16-alpha)-(9Cl);16,17-butylidenedioxy-6,9-difluoro-11-hydroxy-17-(methylthio)androst-4-en-3-one;6,9-Difluor-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-dien-17-carbothioneacid (S)-fluoromethylester; (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate;6-alpha,9-alpha-difluoro-11-beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17beta-carboxylicacid cyanomethyl ester, each optionally in the form of the racemates,enantiomers or diastereomers thereof and optionally in the form of thesalts and derivatives, solvates and/or hydrates thereof.

Particularly preferably the steroid is selected from among budesonide,fluticasone, mometasone, ciclesonide and (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Any reference to steroids includes a reference to any salts orderivatives, hydrates or solvates thereof which may exist. Examples ofpossible salts and derivatives of the steroids may be: alkali metalsalts, such as for example sodium or potassium salts, sulfobenzoates,phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates thereof.

PDE4 inhibitors which may be used are preferably compounds selected fromamong enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),tofimilast, pumafentrin, lirimilast, apremilast, arofyllin, atizoram,oglemilast, tetomilast;5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamide]-8-methoxy-Quinoline(D-4418);5-[N-(3,5-dichloro-1-oxido-4-pyridinyl)-carboxamide]-8-methoxy-2-(trifluoromethyl)-Quinoline(D-4396 (Sch-351591));N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3-yl]glyoxylicacid amide (AWD-12-281 (GW-842470));9-[(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-Purin-6-amine(NCS-613);4-[(2R)-2-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-Pyridine(CDP-840);N-[(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1-phenylpyrrolo[3,2,1-jk][1,4]benzodiazepin-3-yl]-4-Pyridinecarboxamide(PD-168787);4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-2(1H)-Pyridinone(T-440);2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridinyl]-4-(3-pyridinyl)-1(2H)-Phthalazinone (T-2585);(3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine(V-11294A);beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-Isoindole-2-propanamide(CDC-801); Imidazo[1,5-a]pyrido[3,2-e]pyrazine-6(5H)-one,9-ethyl-2-methoxy-7-methyl-5-propyl-(D-22888);5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl]-,(3S,5S)-2-Piperidinon (HT-0712);4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinyl)ethyl]-alpha,alpha-bis(trifluoromethyl)-Benzenemethanol(L-826141);N-(3,5-Dichloro-1-oxo-pyridin-4-yl)-4-difluormethoxy-3-cyclopropylmethoxybenzamide;(−)p-[(4aR*,10bS*)-9-Ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide;(R)-(+)-1-(4-Brombenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidon;3-(Cyclopentyloxy-4-methoxyphenyl)-1-(4-N′—[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidon;cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid];2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one;cis[4-Cyano-4-(3-cyclopropylmethoxy-4-difluormethoxyphenyl)cyclohexan-1-ol];(R)-(+)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetat;(S)-(−)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden]acetat;9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridin;9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridin,optionally in the form of the racemates, enantiomers or diastereomersand optionally in the form of the pharmacologically acceptable acidaddition salts, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theabove-mentioned PDE4-inhibitors might be in a position to form aremeant, for example, salts selected from among the hydrochloride,hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferablyhydrochloride, hydrobromide, hydrosulphate, hydrophosphate,hydrofumarate and hydromethanesulphonate.

LTD4-antagonists which may be used are preferably compounds selectedfrom among montelukast, pranlukast, zafirlukast;(E)-8-[2-[4-[4-(4-Fluorophenyl)butoxy]phenyl]ethenyl]-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one(MEN-91507);4-[6-Acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]-butyricacid (MN-001);1-(((R)-(3-(2-(6,7-Difluor-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-aceticacid;1-(((1(R)-3(3-(2-(2,3-Dichlorthieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid;[2-[[2-(4-tert-Butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid, optionally in the form of the racemates, enantiomers ordiastereomers, optionally in the form of the pharmacologicallyacceptable acid addition salts and optionally in the form of the saltsand derivatives, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theLTD4-antagonists may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.By salts or derivatives which the LTD4-antagonists may be capable offorming are meant, for example: alkali metal salts, such as, forexample, sodium or potassium salts, alkaline earth metal salts,sulphobenzoates, phosphates, isonicotinates, acetates, propionates,dihydrogen phosphates, palmitates, pivalates or furoates.

The EGFR-inhibitors used are preferably compounds selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-Phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-butene-1-yl}amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-butene-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6.7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholine-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-ethoxy-quinoline,4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl]-amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-butene-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2.2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholine-4-yl)-piperidine-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidine-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidine-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidine-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholine-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholine-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,4[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidine-1-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazolin;4-{2-[4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-ethyl}-6-methyl-morpholine-2-one,4-{4-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-cyclohexyl}-1-methyl-piperazine-2-one,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidine-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesuphonyl-piperidine-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidine-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidine-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidine-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazine-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholine-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,4[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4[(3-ethynyl-phenyl)amino]-6-(piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidine-4-yloxy]-7-methoxy-quinazoline,4[(3-ethynyl-phenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidine-4-yloxy}-7-methoxy-quinazoline,4-[(3-chlIoro-4-flIuoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholine-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesuphonyl-piperidine-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidine-4-yloxy)-7-methoxy-quinazoline,3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}-7-ethoxy-quinoline,[4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]-piperazine-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholine-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-(2-{4-[(S)-(2-oxo-tetrahydrofuran-5-yl)carbonyl]-piperazine-1-yl}-ethoxy)-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethoxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[4-((S)-6-methyl-2-oxo-morpholine-4-yl)-butyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,cetuximab, trastuzumab, panitumumab (=ABX−EGF), Mab ICR-62, gefitinib,pelitinib, canertinib and erlotinib, optionally in the form of theracemates, enantiomers or diastereomers thereof, optionally in the formof the pharmacologically acceptable acid addition salts thereof, thesolvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theEGFR-inhibitors may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.

Examples of dopamine agonists which may be used preferably includecompounds selected from among bromocriptine, cabergoline,alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol,ropinirol, talipexol, terguride and viozan. Any reference to theabove-mentioned dopamine agonists within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts and optionally hydrates thereof which may exist. By thephysiologically acceptable acid addition salts which may be formed bythe above-mentioned dopamine agonists are meant, for example,pharmaceutically acceptable salts which are selected from the salts ofhydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid and maleic acid.

Examples of H1-antihistamines preferably include compounds selected fromamong epinastine, cetirizine, azelastine, fexofenadine, levocabastine,loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine,bamipin, cexchlorpheniramine, pheniramine, doxylamine,chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine,ebastine, olopatadine, desloratidine and meclozine. Any reference to theabove-mentioned H1-antihistamines within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts which may exist.

Examples of PAF-antagonists preferably include compounds selected fromamong lexipafant,4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines,6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpho-linyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines.Any reference to the above-mentioned above-mentioned PAF-antagonistsincludes within the scope of the present invention a reference to anypharmacologically acceptable acid addition salts thereof which mayexist.

Examples of non-steroidal anti-inflammatory drugs (NSAIDs) preferablyinclude compounds selected from among Aceclofenac, Acemetacin,Acetylsalicylsaure, Alclofenac, Alminoprofen, Amfenac, Ampiroxicam,Antolmetinguacil, Anirolac, Antrafenin, Azapropazon, Benorilat,Bermoprofen, Bindarit, Bromfenac, Bucloxinsaure, Bucolom, Bufexamac,Bumadizon, Butibufen, Butixirat, Carbasalatcalcium, Carprofen, CholinMagnesium Trisalicylat, Celecoxib, Cinmetacin, Cinnoxicam, Clidanac,Clobuzarit, Deboxamet, Dexibuprofen, Dexketoprofen, Diclofenac,Diflunisal, Droxicam, Eltenac, Enfenaminsaure, Etersalat, Etodolac,Etofenamat, Etoricoxib, Feclobuzon, Felbinac, Fenbufen, Fenclofenac,Fenoprofen, Fentiazac, Fepradinol, Feprazon, Flobufen, Floctafenin,Flufenaminsaure, Flufenisal, Flunoxaprofen, Flurbiprofen,Flurbiprofenaxetil, Furofenac, Furprofen, Glucametacin, Ibufenac,Ibuprofen, Indobufen, Indometacin, Indometacinfarnesil, Indoprofen,Isoxepac, Isoxicam, Ketoprofen, Ketorolac, Lobenzarit, Lonazolac,Lornoxicam, Loxoprofen, Lumiracoxib, Meclofenaminsaure, Meclofen,Mefenaminsaure, Meloxicam, Mesalazin, Miroprofen, Mofezolac, Nabumeton,Naproxen, Nifluminsäure, Olsalazin, Oxaprozin, Oxipinac, Oxyphenbutazon,Parecoxib, Phenylbutazon, Pelubiprofen, Pimeprofen, Pirazolac,Priroxicam, Pirprofen, Pranoprofen, Prifelon, Prinomod, Proglumetacin,Proquazon, Protizininsaure, Rofecoxib, Romazarit, Salicylamid,Salicylsaure, Salmistein, Salnacedin, Salsalat, Sulindac, Sudoxicam,Suprofen, Talniflumat, Tenidap, Tenosal, Tenoxicam, Tepoxalin,Tiaprofensaure, Taramid, Tilnoprofenarbamel, Timegadin, Tinoridin,Tiopinac, Tolfenaminsaure, Tolmetin, Ufenamat, Valdecoxib, Ximoprofen,Zaltoprofen und Zoliprofen.

MRP4-inhibitors used are preferably compounds selected from amongN-acetyl-dinitrophenyl-cysteine, cGMP, cholate, diclofenac,dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone 3-sulphate,dilazep, dinitrophenyl-s-glutathione, estradiol 17-beta-glucuronide,estradiol 3,17-disulphate, estradiol 3-glucuronide, estradiol3-sulphate, estrone 3-sulphate, flurbiprofen, folate,N5-formyl-tetrahydrofolate, glycocholate, glycolithocholic acidsulphate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholicacid sulphate, methotrexate,((E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoicacid), alpha-naphthyl-beta-D-glucuronide, nitrobenzyl mercaptopurineriboside, probenecid, sildenafil, sulfinpyrazone,taurochenodeoxycholate, taurocholate, taurodeoxycholate,taurolithocholate, taurolithocholic acid sulphate, topotecan, trequinsinand zaprinast, dipyridamole, optionally in the form of the racemates,enantiomers, diastereomers and the pharmacologically acceptable acidaddition salts and hydrates thereof.

Examples of JAK inhibitors preferably include compounds selected fromamong Tofacitinib and Ruxolitinib.

Examples of immunesuppressive agents preferably include compoundsselected from among mycophenolate mofetil, mycophenolic acid,azathioprine, cyclosporine, tacrolimus, pimecrolimus, abetimus,gusperimus and leflunomide.

An example of a cytostaticum is cyclophosphamide.

The invention relates more preferably to the use of MRP4-inhibitors forpreparing a pharmaceutical composition for treating respiratorycomplaints, containing the SYK-inhibitors of formula 1 or 1′ andMRP4-inhibitors according to the invention, the MRP4-inhibitorspreferably being selected from among dehydroepiandrosterone 3-sulphate,estradiol 3,17-disulphate, flurbiprofen, indomethacin, indoprofen,taurocholate, optionally in the form of the racemates, enantiomers,diastereomers and the pharmacologically acceptable acid addition saltsand hydrates thereof. The separation of enantiomers from the racematescan be carried out using methods known from the art (e.g. chromatographyon chiral phases, etc.).

By acid addition salts with pharmacologically acceptable acids aremeant, for example, salts selected from among the hydrochlorides,hydrobromides, hydroiodides, hydrosulphates, hydrophosphates,hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates,hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates,hydrooxalates, hydrosuccinates, hydrobenzoates andhydro-p-toluenesulphonates, preferably the hydrochlorides,hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates andhydromethanesulphonates.

The invention further relates to pharmaceutical preparations whichcontain a triple combination of the SYK-inhibitors of formula 1 or 1′,MRP4-inhibitors and another active substance according to the invention,such as, for example, an anticholinergic, a PDE4 inhibitor, a steroid,an LTD4-antagonist or a betamimetic, and the preparation thereof and theuse thereof for treating respiratory complaints.

Compounds which may be used as iNOS inhibitors are compounds selectedfrom among: S-(2-aminoethyl)isothiourea, aminoguanidine,2-aminomethylpyridine, 5,6-dihydro-6-methyl-4H-1,3-Thiazine-2-amine(=AMT), L-canavanine, 2-iminopiperidine, S-isopropylisothiourea,S-methylisothiourea, S-ethylisothiourea, S-methyltiocitrullin,S-ethylthiocitrulline, L-NA (N^(ω)-nitro-L-arginine), L-NAME(Nω-nitro-L-argininemethylester), L-NMMA (N^(G)-monomethyl-L-arginine),L-NIO (Nω-iminoethyl-L-ornithine), L-NIL (Nω-iminoethyl-lysine),(S)-6-acetimidoylamino-2-amino-hexanoic acid (1H-tetrazol-5-yl)-amide(SC-51) (J. Med. Chem. 2002, 45, 1686-1689),N-[[3-(aminomethyl)phenyl]methyl]-Ethanimidamide (=1400W),(S)-4-(2-acetimidoylamino-ethylsulphanyl)-2-amino-butyric acid(GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600),2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine(BYK191023) (Mol. Pharmacol. 2006, 69, 328-337),2-((R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile (WO01/62704),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-6-trifluoromethyl-nicotinonitrile(WO 2004/041794),2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-4-chloro-benzonitrile(WO 2004/041794),2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-benzonitrile(WO 2004/041794),(2S.4R)-2-amino-4-(2-chloro-5-trifluoromethyl-phenylsulphanyl)-4-thiazol-5-yl-butan-1-ol(WO 2004/041794),2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-nicotinonitrile(WO 2004/041794),4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulphanyl)-6-methoxy-nicotinonitrile(WO 02/090332), substituted 3-phenyl-3,4-dihydro-1-isoquinolinamine suchas e.g. (1S.5S.6R)-7-chloro-5-methyl-2-aza-bicyclo[4.1.0]hept-2-en-3-ylamine(ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667),(4R,5R)-5-ethyl-4-methyl-thiazolidin-2-ylideneamine (Bioorg. Med. Chem.2004, 12, 4101), (4R,5R)-5-ethyl-4-methyl-selenazolidin-2-ylideneamine(Bioorg. Med. Chem. Lett. 2005, 15, 1361), 4-aminotetrahydrobiopterine(Curr. Drug Metabol. 2002, 3, 119-121),(E)-3-(4-chloro-phenyl)-N-(1-{2-oxo-2-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-piperidine-1-yl]-ethylcarbamoyl}-2-pyridin-2-yl-ethyl)-acrylamide(FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76),3-(2,4-difluoro-phenyl)-6-[2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine(PPA250) (J. Pharmaco Exp. Ther. 2002, 303, 52-57),3-{[(benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazol-1-yl-pyrimidin-4-yl)-piperazine-1-carboxylate(BBS-1) (Drugs Future 2004, 29, 45-52),(R)-1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-2-carboxylicacid (2-benzo[1,3]dioxol-5-yl-ethyl)-amide (BBS-2) (Drugs Future 2004,29, 45-52) and the pharmaceutical salts, prodrugs or solvates thereof.

Examples of iNOS-inhibitors within the scope of the present inventionmay also include antisense oligonucleotides, particularly thoseantisense oligonucleotides which bind iNOS-coding nucleic acids. Forexample, WO 01/52902 describes antisense oligonucleotides, particularlyantisense oligonucleotides, which bind iNOS coding nucleic acids, formodulating the expression of iNOS. iNOS-antisense oligonucleotides asdescribed particularly in WO 01/52902 may therefore also be combinedwith the PDE4-inhibitors of the present invention on account of theirsimilar effect to the iNOS-inhibitors.

Suitable HMG-CoA reductase inhibitors (also called statins) which may bepreferably used in double or triple combinations with the compounds offormula 1 are selected from among Atorvastatin, Cerivastatin,Flurvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin,Simvastatin, optionally in form of their pharmaceutically available acidaddition salts, prodrugs, solvates or hydrates thereof.

8. FORMULATIONS

The compounds of formula 1 or 1′ according to the invention also haveproperties required for the manufacture of suitable pharmaceuticaldosage forms. These properties include for instance properties relevantfor sufficient bioavailability of the active ingredient, in particularsufficiently high solubilites thereof such as for instance a solubilitythat is >2 μg/ml measured in aqueous solution at pH 6.8.

Suitable forms for administration are for example tablets, capsules,solutions, syrups, emulsions or inhalable powders or aerosols. Thecontent of the pharmaceutically effective compound(s) in each caseshould be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. %of the total composition, i.e. in amounts which are sufficient toachieve the dosage range specified hereinafter.

The preparations may be administered orally in the form of a tablet, asa powder, as a powder in a capsule (e.g. a hard gelatine capsule), as asolution or suspension. When administered by inhalation the activesubstance combination may be given as a powder, as an aqueous oraqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised bythe content of one or more compounds of formula 1 or 1′ according to thepreferred embodiments above.

It is particularly preferable if the compounds of formula 1 or 1′ areadministered orally, and it is also particularly preferable if they areadministered once or twice a day. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules. Suitable suppositories may be made forexample by mixing with carriers provided for this purpose, such asneutral fats or polyethyleneglycol or the derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e.g. lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart fromthe abovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like.

Moreover, lubricants such as magnesium stearate, sodium lauryl sulphateand talc may be used at the same time for the tabletting process. In thecase of aqueous suspensions the active substances may be combined withvarious flavour enhancers or colourings in addition to the excipientsmentioned above.

It is also preferred if the compounds of formula 1 or 1′ areadministered by inhalation, particularly preferably if they areadministered once or twice a day. For this purpose, the compounds offormula 1 or 1′ have to be made available in forms suitable forinhalation. Inhalable preparations include inhalable powders,propellant-containing metered-dose aerosols or propellant-free inhalablesolutions, which are optionally present in admixture with conventionalphysiologically acceptable excipients.

Within the scope of the present invention, the term propellant-freeinhalable solutions also includes concentrates or sterile ready-to-useinhalable solutions. The preparations which may be used according to theinvention are described in more detail in the next part of thespecification.

Inhalable Powders

If the active substances of formula 1 or 1′ are present in admixturewith physiologically acceptable excipients, the followingphysiologically acceptable excipients may be used to prepare theinhalable powders according to the invention: monosaccharides (e.g.glucose or arabinose), disaccharides (e.g. lactose, saccharose,maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g.sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calciumcarbonate) or mixtures of these excipients with one another. Preferably,mono- or disaccharides are used, while the use of lactose or glucose ispreferred, particularly, but not exclusively, in the form of theirhydrates. For the purposes of the invention, lactose is the particularlypreferred excipient, while lactose monohydrate is most particularlypreferred. Methods of preparing the inhalable powders according to theinvention by grinding and micronising and by finally mixing thecomponents together are known from the prior art.

Propellant-Containing Inhalable Aerosols

The propellant-containing inhalable aerosols which may be used accordingto the invention may contain the compounds of formula 1 or 1′ dissolvedin the propellant gas or in dispersed form. The propellant gases whichmay be used to prepare the inhalation aerosols according to theinvention are known from the prior art. Suitable propellant gases areselected from among hydrocarbons such as n-propane, n-butane orisobutane and halohydrocarbons such as preferably fluorinatedderivatives of methane, ethane, propane, butane, cyclopropane orcyclobutane. The propellant gases mentioned above may be used on theirown or in mixtures thereof. Particularly preferred propellant gases arefluorinated alkane derivatives selected from TG134a(1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane)and mixtures thereof. The propellant-driven inhalation aerosols usedwithin the scope of the use according to the invention may also containother ingredients such as co-solvents, stabilisers, surfactants,antioxidants, lubricants and pH adjusters. All these ingredients areknown in the art.

Propellant-Free Inhalable Solutions

The compounds of formula 1 or 1′ according to the invention arepreferably used to prepare propellant-free inhalable solutions andinhalable suspensions. Solvents used for this purpose include aqueous oralcoholic, preferably ethanolic solutions. The solvent may be water onits own or a mixture of water and ethanol. The solutions or suspensionsare adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids.The pH may be adjusted using acids selected from inorganic or organicacids. Examples of particularly suitable inorganic acids includehydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/orphosphoric acid. Examples of particularly suitable organic acids includeascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,succinic acid, fumaric acid, acetic acid, formic acid and/or propionicacid etc. Preferred inorganic acids are hydrochloric and sulphuricacids. It is also possible to use the acids which have already formed anacid addition salt with one of the active substances. Of the organicacids, ascorbic acid, fumaric acid and citric acid are preferred. Ifdesired, mixtures of the above acids may also be used, particularly inthe case of acids which have other properties in addition to theiracidifying qualities, e.g. as flavourings, antioxidants or complexingagents, such as citric acid or ascorbic acid, for example. According tothe invention, it is particularly preferred to use hydrochloric acid toadjust the pH.

Co-solvents and/or other excipients may be added to the propellant-freeinhalable solutions used for the purpose according to the invention.Preferred co-solvents are those which contain hydroxyl groups or otherpolar groups, e.g. alcohols—particularly isopropyl alcohol,glycols—particularly propyleneglycol, polyethyleneglycol,polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols andpolyoxyethylene fatty acid esters. The terms excipients and additives inthis context denote any pharmacologically acceptable substance which isnot an active substance but which can be formulated with the activesubstance or substances in the pharmacologically suitable solvent inorder to improve the qualitative properties of the active substanceformulation. Preferably, these substances have no pharmacological effector, in connection with the desired therapy, no appreciable or at leastno undesirable pharmacological effect. The excipients and additivesinclude, for example, surfactants such as soya lecithin, oleic acid,sorbitan esters, such as polysorbates, polyvinylpyrrolidone, otherstabilisers, complexing agents, antioxidants and/or preservatives whichguarantee or prolong the shelf life of the finished pharmaceuticalformulation, flavourings, vitamins and/or other additives known in theart. The additives also include pharmacologically acceptable salts suchas sodium chloride as isotonic agents. The preferred excipients includeantioxidants such as ascorbic acid, for example, provided that it hasnot already been used to adjust the pH, vitamin A, vitamin E,tocopherols and similar vitamins or provitamins occurring in the humanbody. Preservatives may be used to protect the formulation fromcontamination with pathogens. Suitable preservatives are those which areknown in the art, particularly cetyl pyridinium chloride, benzalkoniumchloride or benzoic acid or benzoates such as sodium benzoate in theconcentration known from the prior art.

For the treatment forms described above, ready-to-use packs of amedicament for the treatment of respiratory complaints are provided,containing an enclosed description including for example the wordsrespiratory disease, COPD or asthma, together with aimidazolyl-pyrimidine according to formula 1 or 1′ and one or morecombination partners selected from those described above.

The invention claimed is:
 1. A method for the treatment of a diseasewhich can be treated by inhibition of the SYK enzyme comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of formula 1 or 1′,

wherein A is either N or CH, wherein Y is either —O— or CH₂, wherein R³is a substituent in ortho- or in meta-position of the pyrazolyl-ring offormula 1 and is selected from the group consisting of linear orbranched —C₁₋₆-alkyl, —C₁₋₆-haloalkyl, —C₃₋₆-cycloalkyl,—C₁₋₄-alkylene-C₃₋₆-cycloalkyl, a five- or six-membered monocyclicheterocycle with 1, 2 or three heteroatoms each independently selectedfrom O, S or N, a nine- to 10-membered bicyclic heterocycle with 1, 2 or3 heteroatoms each independently selected from O, S or N, wherein R³ isoptionally substituted by one, two, three or four substituents eachindependently from each other selected from the group consisting ofhalogen, —C₁₋₃-alkyl, oxo, —CN wherein R² is selected from the groupconsisting of —C₁₋₃-alkyl, —C₁₋₃-haloalkyl, F, Br, Cl, and thepharmaceutically acceptable salts of the aforementioned compounds andwherein the disease is selected from the group consisting of allergicrhinitis, asthma, COPD, B-cell lymphoma, dermatitis, rheumatoidarthritis, ulcerative colitis, lupus erythematodes, lupus nephritis,Crohn's disease, multiple sclerosis, psoriasis, sclerodermy, T-celllymphoma, systemic sclerosis (SSc), and malaria.
 2. The method of claim1, wherein R² is methyl or a pharmaceutically acceptable salt of one ofthe aforementioned compounds.
 3. The method of claim 1, wherein R² is For a pharmaceutically acceptable salt of one of the aforementionedcompounds.
 4. The method of claim 1, wherein A is N or apharmaceutically acceptable salt of one of the aforementioned compounds.5. The method of claim 1, wherein A is CH or a pharmaceuticallyacceptable salt of one of the aforementioned compounds.
 6. The method ofclaim 1, wherein the compound of formula 1 is selected from the groupconsisting of

and a pharmaceutically acceptable salt of one of the aforementionedcompounds.
 7. The method of claim 1, wherein the compound of formula 1is selected from the group consisting of

and a pharmaceutically acceptable salt of one of the aforementionedcompounds.
 8. The method of claim 1, wherein the compound of formula 1is selected from the group consisting of

and a pharmaceutically acceptable salt of one of the aforementionedcompounds.
 9. The method of claim 1, wherein the disease is selectedfrom the group consisting of asthma, COPD, rheumatoid arthritis,systemic sclerosis, ulcerative colitis, Crohn's disease, lupuserythematodes, lupus nephritis, multiple sclerosis and psoriasis. 10.The method of claim 1, wherein the disease is COPD.
 11. The method ofclaim 1, wherein the disease is asthma.